ABSTRACT
An oxidation product (5) formed during the synthesis of BIBN-4096BS (1) was found to be a potent CGRP antagonist (IC50=0.11nM). While 5 was found to be ten-fold less potent than 1, another analog 8 with lower molecular weight containing the oxidized fragment demonstrated twenty-fold higher activity than its parent 7. Alternative conditions which preclude the formation of the oxidation product are described. The activities of 1, 5, 7 and 8 in functional cAMP assay are also discussed.
Subject(s)
Calcitonin Gene-Related Peptide Receptor Antagonists , Piperazines/chemistry , Quinazolines/chemistry , Biological Assay , Inhibitory Concentration 50 , Molecular Structure , Oxidation-Reduction , Piperazines/chemical synthesis , Piperazines/pharmacology , Quinazolines/chemical synthesis , Quinazolines/pharmacologyABSTRACT
[structures: see text] A stereocontrolled racemic synthesis of conformationally restricted analogues 2a and 2b of a potent CGRP receptor antagonist 1 by novel functionalization of 2-substituted octahydropyrido[1,2-a]pyrazin-6-ones is described. The new diastereoselective LDA-promoted alpha-nitration of intermediate lactams established the required trans-configuration in the desired products.
Subject(s)
Benzimidazoles/chemical synthesis , Calcitonin Gene-Related Peptide Receptor Antagonists , Piperazines/chemical synthesis , Piperidines/chemical synthesis , Pyrazines/chemistry , Benzimidazoles/chemistry , Crystallography, X-Ray , Lactams/chemistry , Molecular Conformation , Molecular Structure , Piperazines/chemistry , Piperidines/chemistry , StereoisomerismABSTRACT
Conformationally constrained aryl cyclohexanes and cyclohexenes based on aryl cyclohexanols 1 were prepared. Locking the aryl ring in plane with the cyclohexane moiety provided potent SSRIs 3. Conversely, fixing the aryl ring perpendicular to the cyclohexane ring via a spiro lactone provided balanced 5-HT1A antagonists with mid-nanomolar range SSRI potency (compounds 2).
Subject(s)
Receptor, Serotonin, 5-HT1A/metabolism , Selective Serotonin Reuptake Inhibitors/chemistry , Selective Serotonin Reuptake Inhibitors/metabolism , Serotonin/metabolism , Ligands , Molecular ConformationABSTRACT
The present studies have identified a series of aminotriazines as novel 5-HT(7) receptor antagonists. Compounds 10 and 17 have high affinity for the 5-HT(7) receptor and do not bind to either the 5-HT(2C) or 5-HT(6) receptors. These compounds produce no agonist effects by themselves, and shift the dose-response curve of 5-CT to the right in the manner of an antagonist.
Subject(s)
Receptors, Serotonin/drug effects , Serotonin Antagonists/pharmacology , Triazines/pharmacology , Dose-Response Relationship, DrugABSTRACT
The present studies have identified a series of diaminopyrimidines and diaminopyridines as novel 5-HT(7) receptor ligands. Three regiosiomeric classes of pyrimidines and four regioisomeric classes of pyridines were synthesized and analyzed for binding to the 5-HT(7) receptor. The 5-HT(7) binding affinities of different regioisomers show clearly the structure-activity relationship with position of ring nitrogens.
