ABSTRACT The development of 8-(2,3,3a,4,5,6-hexahydro-1H-phenalen1-yl)-1-phenyl-1,3,8-triaza-spir... more ABSTRACT The development of 8-(2,3,3a,4,5,6-hexahydro-1H-phenalen1-yl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-ones 3 starting from (RS)-8-acenaphten-1-yl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one 1 is reported. The synthesis and the binding affinities at human OFQ and opioid (μ, κ, δ) receptors of the stereoisomers 3a–f are described. In vitro the most selective compound, (1S,3aS)-8-(2,3,3a,4,5,6-hexahydro-1H-phenalen1-yl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one 3c, was found to act as a full agonist at the OFQ receptor in the GTPγ35S binding test. It turned out to be selective versus a variety of other neurotransmitter systems. When tested in vivo following intraperitoneal injection, compound 3c was found to decrease neophobia in a novel environment and to exhibit dose-dependent anxiolytic-like effects in the elevated plus-maze procedure, thus confirming the effects observed following intracerebroventricular infusion of the OFQ peptide in rat.
A model of the rmGlu1 seven-transmembrane domain complexed with a negative allosteric modulator, ... more A model of the rmGlu1 seven-transmembrane domain complexed with a negative allosteric modulator, 1-ethyl-2-methyl-6-oxo-4-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-1,6-dihydro-pyrimidine-5-carbonitrile (EM-TBPC) was constructed. Although the mGlu receptors belong to the family 3 G-protein-coupled receptors with a low primary sequence similarity to rhodopsin-like receptors, the high resolution crystal structure of rhodopsin was successfully applied as a template in this model and used to select residues for site-directed mutagenesis. Three mutations, F801 6.51 A, Y805 6.55 A, and T815 7.39 M caused complete loss of the [ 3 H]EM-TBPC binding and blocked the EM-TBPC-mediated inhibition of glutamate-evoked G-protein-coupled inwardly rectifying K ؉ channel current and [Ca 2؉ ] i response. The mutation W798 6.48 F increased the binding affinity of antagonist by 10-fold and also resulted in a marked decrease in the IC 50 value (4 versus 128 nM) compared with wild type. The V757 5.47 L mutation led to a dramatic reduction in binding affinity by 13-fold and a large increase in the IC 50 value (1160 versus 128 nM). Two mutations, N7474 5.51 A and N7504 5.54 A, increased the efficacy of the EM-TBPC block of the glutamate-evoked [Ca 2؉ ] i response. We observed a striking conservation in the position of critical residues. The residues Val-757 5.47 , Trp-798 6.48 , Phe-801 6.51 , Tyr-805 6.55 , and Thr-815 7.39 are critical determinants of the EM-TBPC-binding pocket of the mGlu1 receptor, validating the rhodopsin crystal structure as a template for the family 3 G-protein-coupled receptors. In our model, the aromatic ring of EM-TBPC might interact with the cluster of aromatic residues formed from Trp-798 6.48 , Phe-801 6.51 , and Tyr-805 6.55 , thereby blocking the movement of the TM6 helix, which is crucial for receptor activation.
Receptor binding activity Receptor binding activity X 0280 Parallel Solution-and Solid-Phase Synt... more Receptor binding activity Receptor binding activity X 0280 Parallel Solution-and Solid-Phase Synthesis of Spirohydantoin Derivatives as Neurokinin-1 Receptor Ligands.-Sets of spirohydantoin derivatives, e.g. (I), are prepared in a parallel fashion using solution-and solid-phase methods. Following the idea of the "needle" concept, the bis(trifluoromethyl)phenyl needle is coupled to all positions available in the core structure and to endow one of the remaining nitrogens with various residues. The solid-supported synthesis for the generation of the third library yields compounds which mainly differ at the piperidine moiety. A subset of NK-1 active compounds of this library, e.g. (Ib) and (Ic), shows moderate to high binding affinities.-(BLEICHER*, K. H.; WUETHRICH, Y.; DE BONI, M.;
The adduct obtained from the achiral isocyanide (I) and TiCl4 (II), presumably possessing the str... more The adduct obtained from the achiral isocyanide (I) and TiCl4 (II), presumably possessing the structure (III), is combined with the keto compounds (IV) to give the hydroxyamides (V) (Passerini-type reaction). No diastereoselectivity is observed with the chiral isocyanide (VIa) or the amino acid derivative (VIb); the adducts (VII) and (VIII) are formed in a 1:1 ratio (in the case of (VIb), only the isomer (VIIb) is isolated from the crude 1:1 reaction mixture). The reaction is applied to a great variety of isocyanides and keto compounds (ca. 30 examples); the yields range from 14% to over 95% with lower values in the case of the more highly functionalized species.
The present invention relates to the compound of formulas (CF DRAWING IN BOPI) and to a novel pro... more The present invention relates to the compound of formulas (CF DRAWING IN BOPI) and to a novel process for the manufacture of compounds of general formula (CF DRAWING IN BOPI) wherein T is a tritium atom; R1 is hydroxy, alkoxy lower alkenyloxy, benzyloxy, hydrogen, deuterium or tritium; R11 is hydrogen, deuterium or tritium optionally, hydroxy or amino and R 2 is a hydrogen atom or optionally tritium orR1 and R2 form a bond. The compounds of general formula I: are ligands for the metabotropic glutamate receptors of group II.
ABSTRACT The development of 8-(2,3,3a,4,5,6-hexahydro-1H-phenalen1-yl)-1-phenyl-1,3,8-triaza-spir... more ABSTRACT The development of 8-(2,3,3a,4,5,6-hexahydro-1H-phenalen1-yl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-ones 3 starting from (RS)-8-acenaphten-1-yl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one 1 is reported. The synthesis and the binding affinities at human OFQ and opioid (μ, κ, δ) receptors of the stereoisomers 3a–f are described. In vitro the most selective compound, (1S,3aS)-8-(2,3,3a,4,5,6-hexahydro-1H-phenalen1-yl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one 3c, was found to act as a full agonist at the OFQ receptor in the GTPγ35S binding test. It turned out to be selective versus a variety of other neurotransmitter systems. When tested in vivo following intraperitoneal injection, compound 3c was found to decrease neophobia in a novel environment and to exhibit dose-dependent anxiolytic-like effects in the elevated plus-maze procedure, thus confirming the effects observed following intracerebroventricular infusion of the OFQ peptide in rat.
A model of the rmGlu1 seven-transmembrane domain complexed with a negative allosteric modulator, ... more A model of the rmGlu1 seven-transmembrane domain complexed with a negative allosteric modulator, 1-ethyl-2-methyl-6-oxo-4-(1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-1,6-dihydro-pyrimidine-5-carbonitrile (EM-TBPC) was constructed. Although the mGlu receptors belong to the family 3 G-protein-coupled receptors with a low primary sequence similarity to rhodopsin-like receptors, the high resolution crystal structure of rhodopsin was successfully applied as a template in this model and used to select residues for site-directed mutagenesis. Three mutations, F801 6.51 A, Y805 6.55 A, and T815 7.39 M caused complete loss of the [ 3 H]EM-TBPC binding and blocked the EM-TBPC-mediated inhibition of glutamate-evoked G-protein-coupled inwardly rectifying K ؉ channel current and [Ca 2؉ ] i response. The mutation W798 6.48 F increased the binding affinity of antagonist by 10-fold and also resulted in a marked decrease in the IC 50 value (4 versus 128 nM) compared with wild type. The V757 5.47 L mutation led to a dramatic reduction in binding affinity by 13-fold and a large increase in the IC 50 value (1160 versus 128 nM). Two mutations, N7474 5.51 A and N7504 5.54 A, increased the efficacy of the EM-TBPC block of the glutamate-evoked [Ca 2؉ ] i response. We observed a striking conservation in the position of critical residues. The residues Val-757 5.47 , Trp-798 6.48 , Phe-801 6.51 , Tyr-805 6.55 , and Thr-815 7.39 are critical determinants of the EM-TBPC-binding pocket of the mGlu1 receptor, validating the rhodopsin crystal structure as a template for the family 3 G-protein-coupled receptors. In our model, the aromatic ring of EM-TBPC might interact with the cluster of aromatic residues formed from Trp-798 6.48 , Phe-801 6.51 , and Tyr-805 6.55 , thereby blocking the movement of the TM6 helix, which is crucial for receptor activation.
Receptor binding activity Receptor binding activity X 0280 Parallel Solution-and Solid-Phase Synt... more Receptor binding activity Receptor binding activity X 0280 Parallel Solution-and Solid-Phase Synthesis of Spirohydantoin Derivatives as Neurokinin-1 Receptor Ligands.-Sets of spirohydantoin derivatives, e.g. (I), are prepared in a parallel fashion using solution-and solid-phase methods. Following the idea of the "needle" concept, the bis(trifluoromethyl)phenyl needle is coupled to all positions available in the core structure and to endow one of the remaining nitrogens with various residues. The solid-supported synthesis for the generation of the third library yields compounds which mainly differ at the piperidine moiety. A subset of NK-1 active compounds of this library, e.g. (Ib) and (Ic), shows moderate to high binding affinities.-(BLEICHER*, K. H.; WUETHRICH, Y.; DE BONI, M.;
The adduct obtained from the achiral isocyanide (I) and TiCl4 (II), presumably possessing the str... more The adduct obtained from the achiral isocyanide (I) and TiCl4 (II), presumably possessing the structure (III), is combined with the keto compounds (IV) to give the hydroxyamides (V) (Passerini-type reaction). No diastereoselectivity is observed with the chiral isocyanide (VIa) or the amino acid derivative (VIb); the adducts (VII) and (VIII) are formed in a 1:1 ratio (in the case of (VIb), only the isomer (VIIb) is isolated from the crude 1:1 reaction mixture). The reaction is applied to a great variety of isocyanides and keto compounds (ca. 30 examples); the yields range from 14% to over 95% with lower values in the case of the more highly functionalized species.
The present invention relates to the compound of formulas (CF DRAWING IN BOPI) and to a novel pro... more The present invention relates to the compound of formulas (CF DRAWING IN BOPI) and to a novel process for the manufacture of compounds of general formula (CF DRAWING IN BOPI) wherein T is a tritium atom; R1 is hydroxy, alkoxy lower alkenyloxy, benzyloxy, hydrogen, deuterium or tritium; R11 is hydrogen, deuterium or tritium optionally, hydroxy or amino and R 2 is a hydrogen atom or optionally tritium orR1 and R2 form a bond. The compounds of general formula I: are ligands for the metabotropic glutamate receptors of group II.
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