NPY is a 36-amino acid peptide which exerts its physiological effects through the activation of a... more NPY is a 36-amino acid peptide which exerts its physiological effects through the activation of a family of G-protein coupled receptors. In vivo and in vitro characterization of the recently cloned rat Y receptor suggests that it is a primary mediator of NPY-induced feeding 5 2-36 32 [D-Trp ]NPY. rat PP, C2-NPY. Northern blot analysis reveals that the Y receptor is widely distributed in the human brain, with the 5 strongest signals detected in the cortex, putamen and caudate nucleus. The chromosomal localization of the human Y receptor, previously 5 shown to be overlapping and in the opposite orientation to the Y receptor, is determined to be 4q31, the same locus as previously 1 demonstrated for the human Y receptor (Herzog et al.,
The Journal of Pharmacology and Experimental Therapeutics, Nov 1, 2009
The presenilin containing gamma-secretase complex is responsible for the regulated intramembraneo... more The presenilin containing gamma-secretase complex is responsible for the regulated intramembraneous proteolysis of the amyloid precursor protein (APP), the Notch receptor, and a multitude of other substrates. gamma-Secretase catalyzes the final step in the generation of Abeta(40) and Abeta(42) peptides from APP. Amyloid beta-peptides (Abeta peptides) aggregate to form neurotoxic oligomers, senile plaques, and congophilic angiopathy, some of the cardinal pathologies associated with Alzheimer's disease. Although inhibition of this protease acting on APP may result in potentially therapeutic reductions of neurotoxic Abeta peptides, nonselective inhibition of the enzyme may cause severe adverse events as a result of impaired Notch receptor processing. Here, we report the preclinical pharmacological profile of GSI-953 (begacestat), a novel thiophene sulfonamide gamma-secretase inhibitor (GSI) that selectively inhibits cleavage of APP over Notch. This GSI inhibits Abeta production with low nanomolar potency in cellular and cell-free assays of gamma-secretase function, and displaces a tritiated analog of GSI-953 from enriched gamma-secretase enzyme complexes with similar potency. Cellular assays of Notch cleavage reveal that this compound is approximately 16-fold selective for the inhibition of APP cleavage. In the human APP-overexpressing Tg2576 transgenic mouse, treatment with this orally active compound results in a robust reduction in brain, plasma, and cerebral spinal fluid Abeta levels, and a reversal of contextual fear-conditioning deficits that are correlated with Abeta load. In healthy human volunteers, oral administration of a single dose of GSI-953 produces dose-dependent changes in plasma Abeta levels, confirming pharmacodynamic activity of GSI-953 in humans.
The Journal of Pharmacology and Experimental Therapeutics, Nov 1, 1998
... CA). IC 50 values were converted to K i values using the Cheng-Prusoff equation (1973). ... F... more ... CA). IC 50 values were converted to K i values using the Cheng-Prusoff equation (1973). ... Footnotes. Send reprint requests to: Dr. Nika Adham, Synaptic Pharmaceutical Corporation, 215 College Road, Paramus, NJ 07652. 1 ...
We have previously shown that infants with pneumonitis caused by Chlamydia trachomatis, an obliga... more We have previously shown that infants with pneumonitis caused by Chlamydia trachomatis, an obligate intracellular bacterium, possess increased percentages of B lymphocytes but not T lymphocytes in their peripheral blood. It was then demonstrated that chlamydiae induce proliferation in vitro of human peripheral blood B lymphocytes and, in the presence of T cells, differentiation of B cells to immunoglobulin-secreting cells. In this study, we show that C. trachomatis (L2 serovar) binds preferentially to 50% of human B lymphocytes from peripheral blood but only to a small percentage, if any, of T cells. Both monocytes and granulocytes bind and ingest chlamydiae. Despite chlamydial binding to B cells and ingestion by monocytes, no uptake by B cells and limited growth (fewer than 0.5% inclusion-containing cells) in monocytes occur. There is a dramatic decrease in the percentage of cells associated with the bacteria after culture. These results are the first demonstration of binding of C....
NPY is a 36-amino acid peptide which exerts its physiological effects through the activation of a... more NPY is a 36-amino acid peptide which exerts its physiological effects through the activation of a family of G-protein coupled receptors. In vivo and in vitro characterization of the recently cloned rat Y receptor suggests that it is a primary mediator of NPY-induced feeding 5 2-36 32 [D-Trp ]NPY. rat PP, C2-NPY. Northern blot analysis reveals that the Y receptor is widely distributed in the human brain, with the 5 strongest signals detected in the cortex, putamen and caudate nucleus. The chromosomal localization of the human Y receptor, previously 5 shown to be overlapping and in the opposite orientation to the Y receptor, is determined to be 4q31, the same locus as previously 1 demonstrated for the human Y receptor (Herzog et al.,
The Journal of Pharmacology and Experimental Therapeutics, Nov 1, 2009
The presenilin containing gamma-secretase complex is responsible for the regulated intramembraneo... more The presenilin containing gamma-secretase complex is responsible for the regulated intramembraneous proteolysis of the amyloid precursor protein (APP), the Notch receptor, and a multitude of other substrates. gamma-Secretase catalyzes the final step in the generation of Abeta(40) and Abeta(42) peptides from APP. Amyloid beta-peptides (Abeta peptides) aggregate to form neurotoxic oligomers, senile plaques, and congophilic angiopathy, some of the cardinal pathologies associated with Alzheimer's disease. Although inhibition of this protease acting on APP may result in potentially therapeutic reductions of neurotoxic Abeta peptides, nonselective inhibition of the enzyme may cause severe adverse events as a result of impaired Notch receptor processing. Here, we report the preclinical pharmacological profile of GSI-953 (begacestat), a novel thiophene sulfonamide gamma-secretase inhibitor (GSI) that selectively inhibits cleavage of APP over Notch. This GSI inhibits Abeta production with low nanomolar potency in cellular and cell-free assays of gamma-secretase function, and displaces a tritiated analog of GSI-953 from enriched gamma-secretase enzyme complexes with similar potency. Cellular assays of Notch cleavage reveal that this compound is approximately 16-fold selective for the inhibition of APP cleavage. In the human APP-overexpressing Tg2576 transgenic mouse, treatment with this orally active compound results in a robust reduction in brain, plasma, and cerebral spinal fluid Abeta levels, and a reversal of contextual fear-conditioning deficits that are correlated with Abeta load. In healthy human volunteers, oral administration of a single dose of GSI-953 produces dose-dependent changes in plasma Abeta levels, confirming pharmacodynamic activity of GSI-953 in humans.
The Journal of Pharmacology and Experimental Therapeutics, Nov 1, 1998
... CA). IC 50 values were converted to K i values using the Cheng-Prusoff equation (1973). ... F... more ... CA). IC 50 values were converted to K i values using the Cheng-Prusoff equation (1973). ... Footnotes. Send reprint requests to: Dr. Nika Adham, Synaptic Pharmaceutical Corporation, 215 College Road, Paramus, NJ 07652. 1 ...
We have previously shown that infants with pneumonitis caused by Chlamydia trachomatis, an obliga... more We have previously shown that infants with pneumonitis caused by Chlamydia trachomatis, an obligate intracellular bacterium, possess increased percentages of B lymphocytes but not T lymphocytes in their peripheral blood. It was then demonstrated that chlamydiae induce proliferation in vitro of human peripheral blood B lymphocytes and, in the presence of T cells, differentiation of B cells to immunoglobulin-secreting cells. In this study, we show that C. trachomatis (L2 serovar) binds preferentially to 50% of human B lymphocytes from peripheral blood but only to a small percentage, if any, of T cells. Both monocytes and granulocytes bind and ingest chlamydiae. Despite chlamydial binding to B cells and ingestion by monocytes, no uptake by B cells and limited growth (fewer than 0.5% inclusion-containing cells) in monocytes occur. There is a dramatic decrease in the percentage of cells associated with the bacteria after culture. These results are the first demonstration of binding of C....
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