Calcium Antagonists 1

Calcium Antagonists
Raimund Mannhold, Abteilung für Klinische Physiologie, Physiologisches Institut, Universität Düsseldorf,
Federal Republic of Germany (Chaps. 1 – 4)
Werner Seitz, BASF Aktiengesellschaft, Main Laboratory, Ludwigshafen, Federal Republic of Germany
(Chap. 5)

1. Introduction . . . . . . . . . . . . . . . . . 1 4. Clinical Application . . . . . . . . . . . . 6

2. Molecular Pharmacology . . . . . . . . 1 5. General Aspects of Chemistry . . . . . 8
2.1. Sites of Action . . . . . . . . . . . . . . . . 1 5.1. Aralkylamines . . . . . . . . . . . . . . . 9
2.2. Structure – Activity Relationships . . . 3 5.2. 1,4-Dihydropyridines . . . . . . . . . . . 10
3. Pharmacodynamics of Calcium An- 5.3. Diphenylalkylamines . . . . . . . . . . . 11
tagonists in Heart and Smooth Muscle 5 6. References . . . . . . . . . . . . . . . . . . 12

1. Introduction
During the 1980s the important bioregulatory
functions of calcium ions (Ca2+ ; in short: cal-
cium) have emerged. In a normal resting cell the
concentration of free calcium is rather low, rang-
ing from 10−8 to 10−6 mol/L. Calcium concen-
trations within the cell are effectively controlled
by calcium channels and calcium pumps located
in the plasmalemma and internal membranes.
External stimuli are able to trigger the opening of
calcium channels, whereby the internal calcium
concentration rises to about 10−5 mol/L. Thus,
binding of calcium to intracellular calcium-
binding proteins is enabled. Activated binding Figure 1. Scheme of calcium regulation in a eukaryotic cell
proteins can now interact with target proteins,
stimulate their enzymatic activities, and trigger
various cellular events. After a kinetic delay,
the channels close and calcium pumps restore 2. Molecular Pharmacology
the initial calcium concentration (Fig. 1). The
ubiquitous role of calcium as second messenger 2.1. Sites of Action
in numerous cellular events ranges from mus-
cle contraction in smooth and striated muscle Calcium antagonists exert their effects by spe-
through glycogen metabolism to synthesis and cific, i.e., receptor-mediated modes of action.
release of neurotransmitters. The existence of different receptor sites accord-
Amongst the numerous compounds interfer- ing to the pronounced chemical heterogeneity of
ing with calcium pathways by different mech- calcium antagonistic compounds is experimen-
anisms and at different sites, two groups are of tally evidenced. Stereoselectivity is one strong
major importance: the calmodulin antagonists indicator for a specific drug action and has
first described by Weiss [1] and the calcium an- been documented for the racemic calcium an-
tagonists first described by Fleckenstein [2]. tagonists verapamil, gallopamil (D 600), preny-
This review is mainly focused on the molecular, lamine, and chiral dihydropyridine derivatives.
pharmacological, and physicochemical proper- Calcium channels are multisubunit metallo-
ties of the calcium antagonists. proteins of a molecular mass of about 180000

c 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

10.1002/14356007.a04 519
2 Calcium Antagonists
Table 1. Classification of calcium antagonists [19–21]

Class I Class II Class III

Class I A Class I B

Nifedipine (−)-Prenylamine (−)-Gallopamil Diltiazem

(±)-Nisoldipine (+)-Prenylamine (+)-Gallopamil Bencyclane
(±)-Niludipine Tiapamil (−)-Verapamil KB 944
(−)-Nitrendipine Flunarizine (+)-Verapamil
(+)-Nitrendipine Fendiline
(±)-Felodipine

[3], [4]. For calcium antagonists of the 1,4-di- obtained [6]. Ligand binding, therefore, is occur-
hydropyridine type receptor sites within the cal- ring at the biologically relevant receptor sites.
cium channel have been identified by various Further substantiation of the receptor concept
groups for smooth muscle [5], [6], heart muscle for calcium antagonists of the dihydropyridine
[7–12], skeletal muscle [13], [14], and brain [9– type was obtained by the development of cal-
12], [15–18] with the aid of radioligand bind- cium agonists interacting with the same bind-
ing studies. According to these investigations ing sites. Positive inotropic and vasoconstrictor
dihydropyridines exhibit rapid, reversible, sat- properties were reported for the compound Bay
urable, and stereoselective binding to their re- k 8644, which could be competitively antago-
ceptor sites, with high affinities in the nanomolar nized by nifedipine [22]. By means of patch
range. Chemical characterization has revealed clamp analysis it could be demonstrated that
heat sensitivity and protein nature of the binding Bay k 8644 increases the mean opening time
sites probably associated with phospholipids. of the single calcium channel. The agonistic
Furthermore, the binding sites require divalent compound has been obtained by simply ex-
cations in order to bind dihydropyridines, as changing the ester group in position 3 of the di-
demonstrated by the effects of different chela- hydropyridine ring by a nitro substituent (see
tors. Reconstitution of binding occurs by the ad- Fig. 3).
dition of Mn2+ , Ca2+ , and Mg2+ (in decreas- Various groups favor calmodulin as a re-
ing order). Calcium antagonists were classified ceptor candidate for at least some of the ac-
according to their binding characteristics to the tions exerted by calcium antagonists [23–27].
dihydropyridine binding site [19–21] (Table 1). Calmodulin is a ubiquitous calcium-dependent
Class I contains the dihydropyridine derivatives regulator protein, which is involved in numer-
and in addition flunarizine, prenylamine, fendi- ous Ca2+ -mediated cellular events. The phar-
line, and tiapamil. The latter differ from the dihy- macological importance of calmodulin inhibi-
dropyridines by becoming weaker competitors tion has first been investigated by the group of B.
in the presence of diltiazem whereas the dihy- Weiss, indicating the calmodulin-binding prop-
dropyridines become more potent competitors. erties of phenothiazines as a biochemical ba-
Class II compounds are verapamil, gallopamil, sis of their antipsychotic effects [1]. The key
and their enantiomers; they exhibiting bipha- role of calmodulin in the regulation of smooth
sic competition profiles representing negative muscle contraction, the potent vasodilator prop-
heterotropic allosteric regulators. Class III drugs erties, and the probably intracellular location
are positive heterotropic allosteric regulators of of at least some sites of calcium antagonistic
the dihydropyridine binding represented by the drug action [28] led to the assumption that rela-
compound diltiazem. However, it remains to be tionships between vasodilating and calmodulin-
clarified whether the allosteric sites regulating binding properties of some calcium antagonists
dihydropyridine binding are identical with the exist [23], [24], [27]. But only in fendiline and
pharmacologically relevant binding sites of ve- prenylamine, binding constants in the micro-
rapamil and diltiazem. In the case of the di- molar range were found. The comparably weak
hydropyridines significant correlations between binding of verapamil and diltiazem probably ex-
binding data of a series of nifedipine analogues cludes a contribution of calmodulin inhibition to
and their inhibition of mechanical responses was the vasodilating properties of these compounds.
 Calcium Antagonists 3

The effects of calcium and calmodulin antago- rion to derive qualitative structure activity re-
nists on the calmodulin-dependent contraction lationships for these compounds. Figure 3 sum-
of chemically skinned vascular smooth muscle marizes the results obtained from investigations
from rabbit renal arteries were investigated [29]. of the two most important calcium antagonists
According to these experiments the vasodilator verapamil and nifedipine in isolated cat papil-
properties of calcium antagonists cannot be ex- lary muscle. In nifedipine [32] the following es-
plained by interference with the calmodulin sys- sential moieties could be detected: (1) the di-
tem. Thus, the pharmacological importance of hydropyridine ring, (2) the secondary nitrogen
calmodulin inhibition for smooth muscle relax- in the heterocycle, (3) a space-filling substituent
ation by calcium antagonists remains to be clar- in the para-position of the dihydropyridine ring,
ified by further investigations; however, a sub- and (4) an ester group in 3 -position of the het-
classification of calcium antagonists based on erocycle. The ortho nitro substituent and the
their differing potency on calmodulin-regulated 5 -ester structure have been shown to be non-
enzyme activities was developed (Table 2). essential. The position of the substituent on the
phenyl ring is of major importance for the drug
Table 2. Subclassification of calcium antagonists, CaM=Calmodulin
potency, which decreases from ortho through
Anti CaM activ- Weak anti CaM Inhibition of meta to para substitution. These results are
ity with putative activity CaM and target in good accordance with in-vivo investigations
functional im- enzymes
portance [33] and they have been substantiated by differ-
ent other groups in intestinal smooth muscle [6]
Prenylamine Verapamil Dihydropyridine
Fendiline Diltiazem derivatives
and in vivo for antihypertensive potency [34].
Bepridil In the verapamil molecule [28], [35–38] the
nitrile group [39], both benzene rings, and the
tertiary amino nitrogen are essential drug moi-
eties, whereas the isopropyl group and the aro-
2.2. Structure – Activity Relationships matic substituents are non-essential. Meta sub-
stitution in the benzene ring near the asymmetric
Beyond stereoselectivity one of the most impor- carbon is optimal for potency; ortho and para
tant criteria in elucidating specific drug actions is substitution diminish potency probably because
the existence of clear-cut structure – activity re- of steric effects. According to extended Hückel
lationships. The number of chemically rather di- molecular orbital calculations the benzene ring
verse compounds with putative calcium antago- and the nitrile group are coplanar in the most sta-
nistic properties steadily increases. Some groups ble conformation [35–41]. These results agree
therefore try to differentiate between specific well with other in-vivo observations indicating
and non-specific calcium antagonists. Experi- that halogen-substituted derivatives are mostly
mental evidence for such a classification is de- effective in lowering blood pressure [42].
rived from electrophysiological [30] and physic- Rather limited data are available on structure-
ochemical investigations [31]. The following activity analyses of diltiazem. The chemical re-
correlations between negative inotropic potency quirements for the vasodilating properties of this
and lipophilicity were obtained [31]: the potency compound in the anesthetized dog were investi-
of non-specific compounds increases with in- gated [43]. This revealed the importance of the
creasing lipophilicity whereas specific calcium amino nitrogen, parallel to that in the verapamil
antagonists exhibit an inverse dependence on molecule. Also in the case of diltiazem the N-
lipophilicity (Fig. 2). dimethyl derivative (secondary amine) as well
Consistently, at least in heart muscle, specific as quaternization products were either far less
calcium antagonists are represented by the com- active or not active compared to the parent com-
pounds verapamil, gallopamil, nifedipine, dilti- pound. In contrast, ring substitution affected the
azem, prenylamine, and fendiline. potency in an opposing manner compared to ve-
The negative inotropic potency of calcium rapamil. Halogen substitution (strong negative
antagonists strongly depends on stimulation inductive effects) decreases the potency. Car-
rate; the determination of amplitude – frequency bonyl substituents in the 3-position of the thiaz-
relationships is therefore an appropriate crite-
4 Calcium Antagonists

Figure 2. Correlations between lipophilicity (RM ) and negative inotropic potency (log 1/ED50 ) of specific calcium antagonists
(open circles) and non-specific negative inotropic compounds (closed circles)

Figure 3. Discrimination between essential and non-essential drug moieties of the two calcium antagonists verapamil and
nifedipine

epine ring strongly increase the vasodilating po- 1) Steric and lipophilic properties determine the
tency of diltiazem. calcium-antagonistic potency of nifedipine.
The electronic, lipophilic, and steric require- 2) Potency of verapamil derivatives mainly de-
ments for drug – receptor interactions of calcium pends on electronic properties, whereas in-
antagonists have been investigated by means creasing steric bulk of ring substituents could
of quantitative structure – activity relationships lead to steric hindrance of the drug – receptor
(Hansch approach) [37]. Correlations of the neg- interaction.
ative inotropic potency of a series of verapa-
mil and nifedipine derivatives with the respec- These results prove the existence of different re-
tive physicochemical substituent parameters re- ceptor sites for calcium antagonists.
vealed the following results:
 Calcium Antagonists 5

3. Pharmacodynamics of Calcium instance, nifedipine and prenylamine (paral-

Antagonists in Heart and Smooth lel shift of AFR)
3) drugs with a preferred action at low stimu-
Muscle lation frequencies, such as bepridil and ben-
cyclane (accentuation of AFR)
Coronary heart disease, arrhythmias, and hyper-
tension are the main indications for the thera- Correlations between these pharmacologi-
peutic application of calcium antagonists. An- cal properties and lipophilic parameters (RM -
tianginal efficacy is based on direct dilatation value) [31] have elucidated an inverse depen-
of the coronary vessels (vasospastic angina) dence on lipophilicity for group 1 and 2 com-
and on a diminution of preload and after- pounds, whereas compounds of group 3 exhibit
load due to a decreased peripheric resistance a positive correlation with lipophilicity probably
(see also, → Antihypertensives). Antihyperten- consistent with non-specific membrane perturb-
sive potency of calcium antagonists is likewise ing actions.
founded on the vasodilator properties on re- At the cellular level, the antiarrhythmic
sistance vessels. Antiarrhythmic properties are action of calcium antagonists is based on
explained, on the one hand, by impairment of the inhibitory effects of these compounds on
pathologic calcium-mediated slow action po- potential-dependent transmembrane ion cur-
tentials and, on the other hand, by their in- rents in working myocardium and in pacemaker
hibitory action at the atrioventricular node (i.e., tissues. In this context sodium- and calcium-
supraventricular tachyarrhythmia). mediated fast action potentials in working my-
Most calcium antagonists exhibit negative in- ocardium have to be differentiated from mainly
otropic actions in vitro, i.e., they diminish the calcium-carried “slow” action potentials, which
contractile force of the isolated myocardium. occur physiologically in impulse generating and
However, the cardiac output of a heart in situ propagating tissue and pathologically in hypoxic
is not necessarily reduced by these compounds. myocardial areas.
This fact has been attributed to reflex sympa- Electrophysiological studies of calcium an-
thetic discharge compensating the direct nega- tagonists on sinoatrial (SA) and atrioventricu-
tive inotropic action of calcium antagonists. The lar (AV) node are of main clinical relevance
mode and site of interference of calcium antago- for the antiarrhythmic therapy with these com-
nists with excitation – contraction coupling (e.c. pounds (→ Antiarrhythmic Drugs). In isolated
coupling) is well understood. Because e.c. cou- SA nodes, both (+)- and (−)-isomers of verap-
pling involves a large set of potential-dependent amil and gallopamil (0.2 – 1.0 µg/mL) reduce
and time-dependent calcium movements, differ- the discharge rate to the point of complete sup-
entiation of calcium antagonists is easily accom- pression of automaticity; different mechanisms
plished by investigating the time and voltage de- are responsible for the effects. The (−)-isomers
pendence of their action. (0.3 – 0.6 µg/mL) slightly reduce the slope of the
The time dependence of inotropic drug ef- slow diastolic depolarization, causing a more
fects is simply characterized by measuring con- effective depression of the maximum veloc-
traction amplitudes at varied stimulation fre- ity of depolarization (MVD) and of the nodal
quencies as compared to control conditions. This conduction velocity until partial or complete
was done for numerous negative inotropic com- nodal conduction blocks occur. The (+)-isomers
pounds [44–48]. According to their influence (1 – 2 µg/mL) do not affect MVD or nodal con-
on the amplitude – frequency relationship (AFR) duction, but obviously shift the threshold volt-
one can differentiate the following three groups: age for the fast depolarization to less negative
voltages.
1) drugs preferentially acting at high stimula-
In isolated SA nodes nifedipine (3 × 10−7 to
tion frequencies, such as verapamil, dilti-
1 × 10−6 mol/L) decreases the discharge rate by
azem, tiapamil, and fendiline (inversion of
reducing both the rate of the slow diastolic de-
AFR)
polarization and the maximal diastolic potential
2) drugs with a negative inotropic action fairly
until intranodal conduction blocks occur.
independent on stimulation frequency as, for
6 Calcium Antagonists

In humans , calcium antagonists normally different groups of calcium channels activated

have no significant effect on sinus node func- by different stimuli, (3) the distinction between
tion. However, in patients with sinus node dys- calcium channels in different tissues and (4) the
function, the same drugs may induce danger- distinction between calcium channels in differ-
ous bradycardia or sinoatrial block. These dif- ent vascular smooth muscles [60].
ferent effects seem to be at least in part caused Tissue Selectivity. Norepinephrine-induced
by the different responsiveness of the normal contractions in rat aorta are more strongly inhib-
and diseased sinus node to changes in automatic ited by nifedipine than by flunarizine, whereas
tone via the baroreceptor reflex. In the AV node, nifedipine is less active in mesenteric artery
conduction and refractoriness are prolonged by [61]. Serotonin-induced contractions are highly
each calcium antagonist to a different degree. sensitive to nimodipine in rabbit basilar artery,
In this regard, gallopamil and verapamil have a but insensitive in saphenous artery [63]. One of
very strong effect, whereas nifedipine in normal the most striking examples of tissue selectivity
doses does not influence AV-nodal conductivity, is concerned with calcium antagonists of the
and tiapamil and diltiazem have an intermediate piperazine type (cinnarizine, flunarizine). These
position between these groups. compounds relax vascular smooth muscle with
For excellent reviews on this topic see [49], high potency, but their calcium-antagonistic po-
[50]. tency in heart muscle is rather negligible.
Calcium antagonists exhibit highly selective Stimulus Selectivity. The strikingly different
actions in smooth muscle preparations. This sensitivities of agonist-induced and potassium-
is revealed by their preferential inhibition of induced contractions to calcium antagonists
depolarization-induced responses described for have already been mentioned. In this context
nitrendipine, nifedipine, and verapamil [51–53]. the use-dependent interaction of calcium en-
Agonist-induced responses exhibit varied try blockers with voltage-dependent channels
sensitivity to calcium-antagonistic compounds. represents marked differences to the interac-
The sensitivity of calcium antagonists pre- tion with receptor-operated channels. The phe-
sumably corresponds to the relative extent to nomenon of use-dependent drug actions has
which calcium is mobilized through potential- first been detected for local anesthetics [64] in
dependent or receptor-operated channels and in- sodium channels and later on for calcium antag-
tracellular stores. Receptor-operated channels onists in heart muscle [65] and in smooth muscle
may exhibit different sensitivities to calcium an- preparations [59].
tagonists depending on receptor and tissue un- In addition to the inhibition of calcium en-
der investigation. Thus, some agonist-induced try interaction by calmodulin, the following al-
contractions have been shown to be equally or ternative mechanisms of the vasodilatation by
even more sensitive to calcium antagonists as calcium antagonists are proposed: inhibition of
compared to potassium-mediated contractions. cAMP phosphodiesterase [66], stimulation of
Equieffective inhibition of norepinephrine and Na+ - und K+ -activated ATPase [67], or a stim-
potassium responses by verapamil were shown ulation of the calcium pump [68]. Calcium an-
in the rat mesenteric artery [54]. Correspond- tagonists must be differentiated further into sub-
ing results were obtained for diltiazem in rabbit groups, e.g., according to their effects [69] or to
mesenteric artery [55]. the occurrence of subtypes of channels [70]. The
Originally, calcium channel blockers have latter could respond to the striking selectivity of
been defined as specific and competitive antago- cinnarizine [71] and flunarizine [72] for smooth
nists of calcium flow into heart and smooth mus- musculature.
cles. Accordingly, mechanical responses and ac- The main pharmacodynamic properties of
tivated calcium uptake are inhibited by calcium calcium antagonists are summarized in Table 3.
antagonists in nearly the same concentration
ranges [56–59].
Selective inhibitory action of calcium antag- 4. Clinical Application
onists in vascular smooth musculature is pre-
sumably based on (1) the presence of different The spectrum of clinical indications for calcium-
mechanisms for activation, (2) the presence of antagonistic compounds is permanently widen-
Table 3. Differentiation of basic pharmacodynamic properties of calcium antagonists. Data in the last column on tissue selectivity for vasodilator potency (coronary artery, K+ -contracture) indicate the factor
by which smooth muscle is more sensitive as compared to heart muscle.
Drug Negative inotropic action Use-dependent action Electrophysiological Vasodilating action
action

EC50 ∗, Frequen- Stereo- Active Develop- Dissociation Negative Negative EC50 ∗, Tissue
mol/L cy depen- selectivity species ment of from specific chrono- dromo- mol/L selectivity
dence negative ino- sites tropic tropic
tropic effect potency potency

Nifedipine 5.1 × 10−7 − (−) base − (−) + (+) 8.13 × 10−9 63

Verapamil 3.5 × 10−6 + (−) cation + + + (+) 2.0 × 10−7 17.5
isomer
Diltiazem 9.8 × 10−6 + d-cis cation + +? (+) ? 2.5 × 10−7 39
presumably
isomer
+
−5
Prenylamine 2.0 × 10 − (−) cation + −/+ (+) ? 1.29 × 10−6 15.5
presumably
isomer
−
−5
Fendiline 5.0 × 10 + (−) cation + ? ? 3.6 × 10−6 14
presumably
isomer
+

∗ EC = effective concentration.
Calcium Antagonists
7
8 Calcium Antagonists

ing. But it is not possible to list therapeutic ap- sensitivity with aging [61]. This was also found
plications that are common to all calcium an- in hypertensive patients [62].
tagonists. The different therapy spectra of the The first clinical empirical reports on cal-
calcium antagonists reflect the differing molec- cium antagonists were concerned with the an-
ular modes of action of these compounds. Vera- tiarrhythmic properties of these compounds. Ve-
pamil, for example, is extraordinarily suitable in rapamil is now well established as the drug of
the treatment of several forms of dysrhythmias choice for treating supraventricular tachycardia.
as well as hypertrophic obstructive cardiomy- Further indications are related to atrial fibrilla-
opathy, whereas nifedipine is not indicated in tion and flutter and sinus tachycardia. Diltiazem
these diseases. Thus, the following brief sum- exhibits antiarrhythmic properties in part resem-
mary of the main clinical applications should be bling the properties of verapamil; doses required
considered in terms of variant validity for the to produce antiarrhythmic effects with nifedip-
individual members of the calcium antagonist ine are not achieved in clinical use.
family. Calcium antagonists have been found to Additional indications for calcium antag-
be useful in treating a wide variety of cardiovas- onists comprise cardiomyopathy, cerebral va-
cular disorders [73]: sospasm, and other vasospastic syndromes.
Angiospastic angina (Prinzmetal)
Angina pectoris, any type 5. General Aspects of Chemistry
Dysrhythmias
Arterial hypertension From a chemical point of view the calcium an-
Left ventricular failure tagonists are a most heterogeneous group of
Acute myocardial infarction compounds. On the basis of structural features
Cardiac preservation and lipophilicities (Table 4) three main sub-
Hypertrophic obstructive cardiomyopathy groups [75], [76] can be differentiated:
Cerebral vasospasm
1) aralkylamines, e.g., verapamil, gallopamil,
One of the most prominent indications of bepridil, tiapamil, diltiazem, caroverine
calcium antagonists is referred to as vasospas- 2) 1,4-dihydropyridines, e.g., nifedipine,
tic or Prinzmetal’s angina. In stable angina cal- nicardipine, nitrendipine, nimodipine, nisol-
cium antagonists apparently are not superior to dipine, and further derivatives
β-blockers. Combination of calcium antagonists 3) diphenylalkylamines, e.g., cinnarizine, flu-
with β-blockers has revealed an impressively in- narizine, prenylamine, fendiline, perhexi-
creased efficacy as compared to monotherapy. line, terodiline
Calcium antagonists are established in the
treatment of arterial hypertension [73], espe- Table 4. Physicochemical properties of calcium antagonists. The last
cially when complications by coronary heart column refers to the degree of ionization of the respective antagonist
at physiological pH (7.4).
disease and/or impaired left ventricular perfor-
mance are involved. In a comparative study Compound RM pK % ionized
on nifedipine and verapamil the acute and Nifedipine 0.21 – –
chronic effects of these compounds on blood Verapamil 0.33 8.73 95.5
Prenylamine 0.51 9.47 99.2
pressure, heart rate, plasma catecholamines, Fendiline 0.68 9.33 98.8
renin – aldosterone, and plasma volume in pa- Diltiazem 0.42 8.06 82.1
tients with mild to moderate hypertension were Perhexiline 0.89 11.09 99.9
Bepridil – 9.39 98.9
investigated [74]. Both drugs did not induce Tiapamil 0.11 8.48 92.3
renin stimulation or fluid retention. Nifedipine,
in contrast to verapamil, increased adrenergic The 1,4-dihydropyridines form a rather
activity which favors the combination of this extensive group of calcium antagonists for
drug with β-blockers. According to the vasodila- which quantitative structure – activity relation-
tor properties of calcium antagonists a clini- ships have been proposed (see Section 2.2).
cally important observation indicates that vas- They are easily distinguished from the other
cular smooth muscle shows markedly increased two groups. Whereas the aralkylamines and
 Calcium Antagonists 9

diphenylalkylamines are protonated at physio- The pharmacological and clinical efficacy of

logical pH, most of the dihydropyridines are bepridil is reviewed [79].
uncharged at pH 7.4 (Table 4). The lipophilic Trade name: Cordium (Organon); contains
character is quantitatively expressed by the RM bepridil monohydrochloride monohydrate.
values determined by reversed-phase TLC. The
diphenylalkylamines can be considered as an- Diltiazem [42399-41-7] [80], cis-(+)-
other chemical subgroup with a bulky lipophilic 3-acetoxy-5-(2-dimethylaminoethyl)-2,3-di-
diphenyl moiety separated by two or three car- hydro-2-(4-methoxyphenyl)-1,5-benzothi-
bon atoms from a basic nitrogen atom. azepin-4 (5H)-one, C22 H26 N2 O4 S, M r 414.5;
the hydrochloride [33286-22-5]melts at 212 ◦ C
(decomp.).
5.1. Aralkylamines
Verapamil and Gallopamil. Verapamil
[52-53-9] [77], (±)-5-[N-(3,4-dimeth-
oxyphen-ethyl)-N-methylamino]-2-(3,4-di-
methoxyphenyl)-2-isopropyl-valeronitrile,
C27 H38 N2 O4 , M r 454.6; the hydrochloride
[152-11-4]melts at 139.5 –140.5 ◦ C.
Trade names: Herbesser (Tanabe Seiyaku),
Dilzem (Goedecke), Cardizem (Marion); con-
tain diltiazem hydrochloride.

Caroverine [23465-76-1] [81], 1-(2-di-

ethylaminoethyl)-3-(4-methoxybenzyl)-1,2-di-
hydro-2- quinoxalinone, C22 H27 N3 O2 , M r
365.5, mp 69 ◦ C.
Trade names: Isoptin (Knoll), Cardibeltin
(Pharma Schwarz), Cordilox (Abbott), Calan
(Searle), Vasolan (Eisai); contain verapamil
hydrochloride.
Gallopamil [16662-47-8] [77], 5-[N-
(3,4-dimethoxyphenethyl)-N-methylami-
Caroverine is being used clinically as a spas-
no]-2-(3,4,5-trimethoxyphenyl)-2-isopropyl-
molytic. Caroverine fumarate is now under de-
valeronitrile, C28 H40 N2 O5 , M r 484.6;
velopment (pre-registration) as calcium antag-
the hydrochloride [16662-46-7]melts at
onist. The pharmacological properties are re-
145 – 148 ◦ C.
viewed [82].
Trade name: Procorum (Chemische Werke
Trade names: Spadon (Donau-Pharmazie),
Minden); contains gallopamil hydrochloride.
Spasmium (Medichemie, CH).
Bepridil [64706-54-3] [78], (±)-N-(3-
isobutoxy-2-pyrrolidin-1-yl-propyl)-N-phenyl- Tiapamil [57010-31-8] [83], N-(3,4-
benzylamine, C24 H34 N2 O, M r 366.3; the dimethoxyphenethyl)-2-(3,4-dimethoxy-
monohydrochloride monohydrate [74764-40-2] phenyl)-N-methyl-m-dithiane-2-propylamin-
melts at 88 – 91 ◦ C. 1,1,3,3-tetra-oxide, C26 H37 NO8 S2 , M r 555.7;
the hydrochloride [57010-32-9]melts at
167 – 169 ◦ C.

Bepridil is a long-acting (half-life 42 h) an-

tianginal agent with antiarrhythmic properties.
10 Calcium Antagonists

Tiapamil is structurally related to verapa- from nifedipine and nitrendipine by its predom-
mil. It is a calcium antagonist with antianginal, inant cerebral vasodilating effects. It prevents
antiarrhythmic and antihypertensive activities. the spasm of brain vessels without considerable
First launch is expected for 1986. decrease of blood pressure. Nimodipine is un-
Proprietary name: Larocord (Hoffmann-La der clinical development and appears effective in
Roche). treatment after subarachnoid hemorrhage, cere-
brovascular insufficiency, and migraine [90].
Trade name: Nimotop (Bayer).
5.2. 1,4-Dihydropyridines
Nisoldipine [63675-72-9] [91], (±)-
Nifedipine [21829-25-4] [84], di- isobutyl methyl 1,4-dihydro-2,6-dimethyl-
methyl 1,4-dihydro-2,6-dimethyl-4-(2- 4-(2-nitrophenyl)pyridine-3,5-dicarboxylate,
nitrophenyl)pyridine- 3,5-dicarboxylate, C20 H24 N2 O6 , M r 388.4, mp 140 – 142 ◦ C. The
C17 H18 N2 O6 , M r 346.3, mp 172 – 174 ◦ C. The pharmacological properties of nisoldipine dif-
chemical structures of nifedipine and other di- fer substantially from those of nifedipine and
hydropyridines are shown in Table 5. nitrendipine. It acts preferentially on vascular
Trade names: Adalat (Bayer), Procardia smooth muscle, leading to lowering of the total
(Pfizer), Duranifin (Durachemie), Pidilat peripheral resistance. Nisoldipine is the most
(Giulini Pharma). potent vasodilator known to act by inhibiting
transmembrane calcium influx. As a powerful
Nicardipine [55985-32-5] [85], (±)2-(N- and fast-acting vasodilator without significant
methylbenzylamino)ethyl methyl 1,4-dihydro- side effects nisoldipine should be useful in treat-
2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5- ing cardiac failure and hypertension [92].
dicarboxylate, C26 H29 N3 O6 , M r 479.5; the Manufacturer: Bayer, first launch expected
hydrochloride [54527-84-3] is isolated in two 1987.
crystalline forms: α-form, mp 168 – 170 ◦ C and
β-form, mp 179 – 181 ◦ C. Niludipine [22609-73-0] [93], bis-(2-
Nicardipine hydrochloride is a calcium an- propoxyethyl) 1,4-dihydro-2,6-dimethyl-4-
tagonistic vasodilator with short half-life, being (3-nitrophenyl)pyridine-3,5-dicarboxylate,
developed for use in hypertension and angina. It C25 H34 N2 O8 , M r 490.6, mp 83 – 86 ◦ C, is a
was launched 1981 for cerebrovascular insuffi- nifedipine analogue with greater vasodilatory
ciency and hypertension [86]. activity and with less cardiac depression. The
Trade names: Perdipine (Yamanouchi), results of a clinical trial suggest that niludipine
Nicodel (Mitsui). is a safe antianginal calcium antagonist with
broad effectiveness for various types of angina
Nitrendipine [39562-70-4] [87], (±)- pectoris [94].
ethyl methyl 1,4-dihydro-2,6-dimethyl-4- Manufacturer: Bayer, first launch expected
(3-nitrophenyl)pyridine-3,5-dicarboxylate, 1986.
C18 H20 N2 O6 , M r 360.2, mp 158 – 159 ◦ C, acts
as a coronary vasodilator with pronounced anti- Felodipine [72509-76-3] [95], (±)-ethyl
hypertensive efficacy. The duration of action is methyl 1,4-dihydro-2,6-dimethyl-4-(2,3-
significantly longer than that of nifedipine [88]. dichlorophenyl)pyridine-3,5-dicarboxylate,
Nitrendipine was launched 1985 as a once-daily C18 H19 Cl2 NO4 , M r 384.3, mp 145 ◦ C, is a
antihypertensive without tachycardial side ef- peripheral vasodilator with antihypertensive ac-
fects. tivity. Compared to nifedipine it appears more
Trade names: Bayotensin (Bayropharm), potent, shows less cardiodepressive potency,
Baypress (Bayer). and the effect seems longer-lasting. Felodipine
appears to be an active antianginal drug and is
Nimodipine [66085-59-4] [89], (±)-isopro- effective in the treatment of hypertension and
pyl 2-methoxyethyl 1,4-dihydro-2,6-dimethyl- congestive heart failure [96].
4-(3-nitrophenyl)pyridine-3,5-dicarboxylate, Manufacturer: Hässle (Sweden), phase III
C21 H26 N2 O7 , M r 418.2, mp 125 ◦ C, differs clinical trials, first launch 1985.
 Calcium Antagonists 11
Table 5. Structural formulas of some 1,4-dihydropyridine derivatives

Nilvadipine [75530-86-6] [97], (±)-5- Darodipine lowers blood pressure and heart
isopropyl 3-methyl 2-cyano-6-methyl-4-(3- rate without depressing an ejection phase param-
nitrophenyl) eter of myocardial contractility. The wide sepa-
ration between negative chronotropic and nega-
tive inotropic effects could present a therapeutic
advantage of darodipine [100].
Manufacturer: Sandoz, phase II clinical tri-
als.

-1,4-dihydropyridine-3,5-dicarboxylate, 5.3. Diphenylalkylamines

C19 H19 N3 O6 , M r 385.4, mp 130 – 131 ◦ C, is
a new dihydropyridine derivative and possesses Prenylamine and Fendiline. Prenylamine
the advantage over nifedipine of having light [390-64-7] [101], (±)-N-(2-benzhydrylethyl)-
stability in solution. Compared with other di- α-methyl-phenethylamine, C24 H27 N, M r 329.5,
hydropyridines, the duration of the effects of nil- mp 38 – 40 ◦ C; the lactate [69-43-2] melts at
vadipine is 2 to 3 times longer. Nilvadipine will 137 – 140 ◦ C.
be beneficial in various cardiocirculatory disor-
ders and particularly promising in the treatment
of cerebrovascular spasm and angina pectoris
[98].
Manufacturer: Fujisawa Pharmaceutical;
phase III clinical trials.

Darodipine [72803-02-2] [99], di-

ethyl 4-(2,1,3-benzoxadiazol-4-yl)-1,4-di- Proprietary names: Segontin (Hoechst),
hydro-2,6-dimethylpyridine-3,5-dicarboxylate, Synadrin (Hoechst, UK).
C19 H21 N3 O5 , M r 371.2, mp 153 – 155 ◦ C. Fendiline [13042-18-7] [102], (±)-N-
(2-benzhydrylethyl)-α-methyl-benzylamine,
C23 H25 N, M r 315.5; the hydrochloride
[13636-18-5] melts at 204 – 205 ◦ C.
Proprietary name: Sensit (Thiemann).
12 Calcium Antagonists

Perhexiline [6621-47-2] [103], (±)-2-(2,2- 3. D. R. Ferry, A. Goll, H. Glossmann, Naunyn

dicyclohexylethyl)piperidine, C19 H35 N, M r Schmiedeberg’s Arch. Pharmacol. 323 (1983)
277.5; the maleate [6724-53-4] melts at 189 ◦ C. 292.
4. J. C. Venter, C. M. Fraser, C. Y. Jung, G.
Bolger, D. J. Triggle, J. Biol. Chem. 258
(1983) 9344.
5. C. R. Triggle, D. K. Agrawal, G. T. Bolger,
E. E. Daniel, C. Y. Kwan, E. M. Luchowski,
D. J. Triggle, Can. J. Physiol. Pharmacol. 60
Proprietary name: Pexid (Merrell). (1982) 1738.
6. G. T. Bolger, P. Gengo, R. Klockowski, E.
Cinnarizine and Flunarizine. Cinnarizine Luchowski, H. Siegel, R. A. Janis, A. M.
[298-57-7] [104], (E)-1-cinnamyl-4-(diphenyl- Triggle, D. J. Triggle, J. Pharmacol. Ther. 225
methyl)piperazine, C26 H28 N2 , M r 368.5; the (1983) 291.
hydrochloride melts at 192 ◦ C (decomp.). 7. P. Bellemann, D. R. Ferry, F. Lübbecke, H.
Glossmann, Arzneim. Forsch./Drug Res. 31
(1981) 2064.
8. J. G. Sarmiento, R. A. Janis, R. A. Colvin, D. J.
Triggle, A. M. Katz, J. Mol. Cell. Cardiol. 15
(1983) 135.
9. K. M. M. Murphy, S. H. Snyder, Eur. J.
Pharmacol. 77 (1982) 201.
10. F. J. Ehlert, E. Itoga, W. R. Roeske, H. J.
Yamamura, Biochem. Biophys. Res. Commun.
104 (1982) 937.
Trade name: Stutgeron (Janssen). 11. P. Bellemann, D. Ferry, F. Lübbecke, H.
Flunarizine [52468-60-7] [105], (E)-1- Glossmann, Arzneim. Forsch./Drug Res. 32
cinnamyl-4-[bis-(4-fluorophenyl)methyl]piper- (1982) 361.
azine, C26 H26 F2 N2 , M r 404.5; the dihydro- 12. H. Glossmann, D. R. Ferry, F. Lübbecke, R.
chloride [30484-77-6]melts at 251.5 ◦ C. Mewes, F. Hofmann, J. Receptor Res. 3
Trade name: Sibelium (Janssen). (1983) 45.
13. D. R. Ferry, H. Glossmann, FEBS Lett. 148
Terodiline [15793-40-5] [106], (±)- (1982) 331.
N-tert-butyl-1-methyl-3,3-diphenylpropyl- 14. H. Glossmann, D. R. Ferry, Naunyn
Schmiedeberg’s Arch. Pharmacol. 323 (1983)
amine, C20 H27 N, M r 281.4; the hydro-
279.
chloride[7082-21-5] melts at 178 – 180 ◦ C.
15. P. J. Marangos, J. Patel, Ch. Miller, A. M.
Martino, Life Sci. 31 (1982) 1575.
16. K. M. M. Murphy, R. J. Gould, B. L. Largent,
S. H. Snyder, Proc. Natl. Acad. Sci. 80 (1983)
860.
17. R. J. Gould, K. M. M. Murphy, S. H. Snyder,
Trade name: Bicor (Recip, Sweden). Proc. Natl. Acad. Sci. 79 (1982) 3656.
18. D. R. Ferry, H. Glossmann, Naunyn
Schmiedeberg’s Arch. Pharmacol. 321 (1982)
80.
6. References 19. H. Glossmann, D. R. Ferry, in: A.
Fleckenstein, K. Hashimoto, M. Herrmann, A.
1. R. M. Levin, B. Weiss, Mol. Pharmacol. 13
Schwartz, L. Seipel (eds.) Drug Development
(1977) 690.
2. A. Fleckenstein, H. Kammermeier, J. J. and Evaluation, vol. 9, New Calcium
Döring, H. J. Freund, Z. Kreislaufforsch. 56 Antagonists, Recent Developments and
(1967) 716. A. Fleckenstein: Prospects, Gustav Fischer Verlag,
Calciumantagonism in Heart and Smooth Stuttgart-New York 1983, pp. 63 – 68.
Muscle, Wiley Interscience, New York 1983.
 Calcium Antagonists 13

20. H. Glossmann, D. R. Ferry, F. Lübbecke, R. 39. R. Mannhold, unpublished results.

Mewes, F. Hofmann, Trends Pharmacol. Sci. 40. H.-D. Höltje, R. Mannhold, R. Rodenkirchen,
3 (1982) 431. R. Bayer, Naunyn Schmiedeberg’s Arch.
21. D. R. Ferry, H. Glossmann, Br. J. Pharmacol. Pharmacol. 316 (1981) R 33.
78 (1983) 81 p. 41. H.-D. Höltje, Arch. Pharm. (Weinheim) 315
22. M. Schramm, G. Thomas, R. Towart, G. (1982) 317.
Franckowiak, Nature 303 (1983) 535. 42. H. Haas, E. Busch, Arzneim. Forsch./Drug
23. H. Hidaka, M. Asano, T. Tanaka, Mol. Res. 17 (1967) 257.
Pharmacol. 20 (1981) 571. 43. T. Nagao, M. Sato, H. Nakajima, A.
24. H. Hidaka, T. Yamaki, M. Naka, T. Tanaka, H. Kiyomoto, Chem. Pharm. Bull. 21 (1973) 92.
Hyashi, R. Kobayashi, Mol. Pharmacol. 17 44. R. Bayer, R. Hennekes, R. Kaufmann, R.
(1979) 66. Mannhold, Naunyn Schmiedeberg’s Arch.
25. M. Kanamori, M. Naka, M. Asano, H. Hidaka,
Pharmacol. 290 (1975) 49.
J. Pharmacol. Exp. Ther. 217 (1981) 494.
45. R. Bayer, R. Rodenkirchen, T. Ehara, R.
26. P. M. Epstein, K. Fiss, R. Hachisu, D. M.
Mannhold, Naunyn Schmiedeberg’s Arch.
Andrenyak, Biochem. Biophys. Res. Commun.
Pharmacol. 293 (1976) R 21.
105 (1982) 1142.
27. J. D. Johnson, P. L. Vaghy, T. H. Crouch, J. D. 46. R. Rodenkirchen, Naunyn Schmiedeberg’s
Potter, A. Schwartz, in H. Yoshida, Y. Arch. Pharmacol. 307 (1979) R 40.
Hagihara, S. Ebashi (eds.): Advances in 47. R. Mannhold: Kalziumantagonisten vom Typ
Pharmacology and Therapeutics II. Vol. 3, der aliphatischen Amine und
Cardio-Renal and Cell Pharmacology, strukturverwandte herzaktive Pharmaka.
Pergamon Press, Oxford-New York 1982, Untersuchungen zur pharmakologischen und
p. 121. physikalisch-chemischen Charakterisierung.
28. R. Mannhold, R. Steiner, W. Haas, R. Verlag Dr. Peter Mannhold, Düsseldorf 1983,
Kaufmann, Naunyn Schmiedeberg’s Arch. p. 1.
Pharmacol. 302 (1978) 217. 48. R. Bayer, R. Rodenkirchen, R. Kaufmann, J. H.
29. V. A. W. Kreye, J. C. Rüegg, F. Hofmann, Lee, R. Hennekes, Naunyn Schmiedeberg’s
Naunyn Schmiedeberg’s Arch. Pharmacol. Arch. Pharmacol. 301 (1977) 29.
323 (1983) 85. 49. L. Seipel, G. Breithardt, Cardiol. 69 (1982)
30. M. Kohlhardt, B. Bauer, H. Krause, A. Suppl. 1, 105.
Fleckenstein, Pflügers Arch. Gesamte Physiol. 50. N. Taira, in A. Fleckenstein, K. Hashimoto, M.
Menschen Tiere 335 (1972) 309. Herrmann, A. Schwartz, L. Seipel (eds.): Drug
31. R. Rodenkirchen, R. Bayer, R. Mannhold, Development and Evaluation, vol. 9, New
Progr. Pharmacol. 5 (1982) 9. Calcium Antagonists, Recent Developments
32. R. Rodenkirchen, R. Bayer, R. Steiner, F. and Prospects, G. Fischer Verlag,
Bossert, H. Meyer, E. Möller, Naunyn Stuttgart-New York 1983, p. 37.
Schmiedeberg’s Arch. Pharmacol. 310 (1979) 51. R. Towart, J. Cardiovasc. Pharmacol. 4
69. (1982) 895.
33. B. Loev, M. M. Goodman, K. M. Snader, R. 52. A. Grün, A. Fleckenstein, Arzneim.
Tedeschi, E. Macko, J. Med. Chem. 17 (1974) Forsch./Drug Res. 22 (1972) 334 – 344.
956. 53. S. Mras, N. Sperelakis, Blood Vessels 18
34. F. Bossert, H. Horstmann, H. Meyer, W. Vater, (1981) 196.
Arzneim. Forsch./Drug Res. 29 (1979) 226. 54. K. Kondo, H. Suzuki, T. Okuno, M. Suda, T.
35. R. Mannhold, Dissertation, Universität Saruta, Arch. Int. Pharmacodyn. 245 (1980)
Düsseldorf 1977. 211.
36. R. Mannhold, R. Bayer, Naunyn 55. C. Cauvin, K. Saida, C. van Breemen, J.
Schmiedeberg’s Arch. Pharmacol. 293 (1970) Cardiovasc. Pharmacol. 4 (1982) 287.
R 21. 56. C. Cauvin, R. Loutzenhiser, C. van Breemen,
37. R. Mannhold, R. Steiner, R. Rodenkirchen, R.
Ann. Rev. Pharmacol. Toxicol. 23 (1983) 373.
Kaufmann, IUPAC-IUPHAR Symposium on
57. K. D. Meisheri, O. Hwang, C. van Breemen, J.
Biological Activity and Chemical Structure,
Membr. Biol. 59 (1981) 19.
Noordwijkerhout (NL) 1977.
38. R. Mannhold, P. Zierden, R. Bayer, R. 58. S. Thorens, G. Häusler, Eur. J. Pharmacol. 54
Rodenkirchen, R. Steiner, Arzneim. (1979) 79.
Forsch./Drug Res. 5 (1981) 773.
14 Calcium Antagonists

59. T. Godfraind, D. Dieu, J. Pharmacol. Exp. Verduyn, Pharmatherapeutica 4 (1985) no. 4,

Ther. 217 (1981) 520. 195 – 222.
60. C. van Breemen, A. Mangel, M. Fahim, K. D. 80. Tanabe Seiyaku, DE 1805714, 1968.
Meisheri, Am. J. Cardiol. 49 (1982) 507. 81. Donau-Pharmazie, US 3028384, 1962 (Zellner
61. T. Godfraind, R. C. Miller, Circ. Res. 52 et al.).
(1983) Suppl. I, 81. 82. Y. Ishida, H. Ozaki, S. Shibata, Br. J.
62. F. R. Bühler, L. Hulthen, W. Kiowski, P. Bolli, Pharmacol. 71 (1980) 343 – 348.
in Clin. Science (Suppl. I), 9th Scientific 83. Hoffmann-La Roche, CH 18030/73, 1973.
Meeting of the ISH, Mexico City, Feb. 21 – 24, 84. Bayer, DE 1670827, 1967 (F. Bossert, W.
1982. Vater).
63. R. Towart, Circ. Res. 48 (1981) 650. 85. Yamanouchi, JP-Kokai 74109384, 1967 (M.
64. P. Heistracher, Naunyn Schmiedeberg’s Arch. Iwanami et al.); DE-OS 2407115, 1974 (M.
Pharmacol. 269 (1971) 199. Murakami et al.).
65. T. Ehara, R. Kaufmann, J. Pharmacol. Exp. 86. T. Takenaka, J. Handa, Int. J. Clin. Pharmacol.
Ther. 207 (1978) 49. L. Rosenberger, D. J. Ther. Toxicol. 17 (1979) 1 – 11.
Triggle, in G. B. Weiss (ed.): Calcium and 87. Bayer, DE 2117573, 1971 (H. Meyer, F.
Drug Action, Plenum Press, New York 1978, Bossert).
p. 3. 88. L. Andren, L. Hansson, L. Oroe, T. Ryman, J.
66. N. Sakamoto, M. Terai, H. Maeno, Biochem. Cardiovasc. Pharmacol. 4 (1982) , Suppl. 3,
Pharmacol. 27, (1978) 1269. 387 – 391.
67. M. Pan, R. A. Janis, Fed. Proc. Fed. Am. Soc. 89. Bayer, DE 2117571, 1971 (H. Meyer et al.);
Exp. Biol. 41 (1982) 1483. DE-OS 2815578 (1979).
68. K. Hermsmeyer, R. Mason, Fed. Proc. Fed. 90. K. Satoh, M. Kawada, Y. Wada, N. Taira,
Am. Soc. Exp. Biol. 41 (1982) 1483. Arzneim. Forsch./Drug Res. 34 (I) (1984)
69. M. Spedding, J. Cardiovasc. Pharmacol. 4 no. 5, 563 – 568.
(1982) 973. 91. Bayer, DE-OS 2549568, 1975 (E. Wehinger et
70. P. V. Kaplita, D. J. Triggle, Biochem. al.).
Pharmacol. 32 (1983) 65. 92. S. Kazda et al., Arzneim. Forsch./Drug Res.
71. A. Broekaert, T. Godfraind, Eur. J. Pharmacol. 30 (II) (1980) 2144 – 2162.
53 (1979) 281. M. B. Emanuel, J. A. Will, 93. Bayer, DE-OS 2670824, 1967 (F. Bossert, W.
Proc. Roy. Soc. Med. 70 (1977) Suppl. 8, 7. Vater).
72. J. M. van Nueten, J. van Beek, P. A. J. Janssen, 94. H. Yasuda et al., Arzneim. Forsch./Drug Res.
Arzneim. Forsch./Drug Res. 28 (1978) 2082. 34 (I) (1984) no. 5, 614 – 619.
M. Borgers, E. Ghoos, F. Thoné, J. M. van 95. A. B. Hässle, EP 7293, 1979 (P. B. Berntsson
Nueten, Blood Vessels 17 (1980) 123. et al.).
73. P. D. Henry, Am. J. Cardiol. 46 (1980) 1047. 96. G. Leonetti et al., J. Cardiovasc. Pharmacol.
74. E. Agabiti-Rosei, C. Alicandri, M. Beschi, M. 6 (1984) 392 – 398.
Castellano, R. Fariello, G. Romanelli, M. L. 97. Fujisawa Pharmaceutical, DE-OS 2940833,
Muiesan, L. Corea, G. Muiesan, in T. 1979 (Y. Sato).
Godfraind, A. Albertini, R. Paoletti (eds.): 98. G. J. Gross, D. C. Warltier, H. F. Hardman, J.
Calcium Modulators, Elsevier Biomedical Cardiovasc. Pharmacol. 6 (1984) 61 – 67.
Press, Amsterdam 1982, p. 257. 99. Sandoz, EP-A 150, 1978 (P. Neumann).
75. M. Spedding, Trends Pharmacol. Sci. 6
100. R. P. Hof, G. Scholtysik, J. Cardiovasc.
(1985) 109 – 114.
Pharmacol. 5 (1984) 176 – 183.
76. P. A. van Zwieten, Arzneim. Forsch./Drug Res.
101. Hoechst, DE 1111642, 1958 (G. Erhart).
35 (I), (1985) no. 1 a, 298 – 301.
102. Chinoin, DE 1171930, 1962.
77. Knoll AG, DE 1154810, 1961 (F. Dengel).
103. Richardson-Merrell, US 3038905, 1960.
78. CERM, DE-OS 2310918, 1973 (R. Y.
104. Janssen, DE 1086235, 1957.
Mauvernay et al.), US Re 30577, 1981 (Busch
105. Janssen, US 3773939, 1968.
et al.).
106. Recip, GB 923942, 1963.
79. J. S. Alpert, P. Coumel, K. Greeff, D. M.
Krikler, W. J. Remme, E. Schönbaum, C. W.