ABSTRACT
A series of thiazole based 5HT(7) ligands has been identified from screening. Optimisation of the pendent aryl group and modification of the core gave a related series of high affinity, selective thiopyridine based 5HT(7) ligands, the most active of which behaves as a partial agonist.
Subject(s)
Pyridines/chemical synthesis , Pyridines/pharmacology , Receptors, Serotonin/chemistry , Receptors, Serotonin/metabolism , Thiazoles/chemical synthesis , Thiazoles/pharmacology , Cells, Cultured , Humans , Ligands , Serotonin/metabolism , Serotonin Receptor Agonists/chemistry , Serotonin Receptor Agonists/pharmacology , Structure-Activity Relationship , beta-Lactamases/metabolismABSTRACT
Novel (E)-N(1)-(benzyl)cinnamamidines were prepared and evaluated as NR2B subtype NMDA receptor ligands. Excellent affinity was achieved by appropriate substitution of either phenyl ring. The 2-methoxybenzyl compound 1h had approximately 1,000-fold lower IC(50) in NR2B than NR2A-containing cells. Replacement of the styryl unit by 2-naphthyl was well tolerated.
Subject(s)
Amidines/chemical synthesis , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Amidines/metabolism , Benzamidines/chemical synthesis , Benzamidines/metabolism , Drug Evaluation, Preclinical , Humans , Naphthalenes/chemical synthesis , Naphthalenes/metabolism , Protein Binding , Radioligand Assay , Receptors, N-Methyl-D-Aspartate/metabolism , Structure-Activity RelationshipABSTRACT
A novel series of benzamidines was synthesized and shown to exhibit NR2B-subtype selective NMDA antagonist activity. Compound 31 is orally active in a carrageenan-induced rat hyperalgesia model of pain and shows no motor coordination side effects.
