ABSTRACT
A novel series of mGluR2 positive allosteric modulators (PAMs), 1-[(1-methyl-1H-imidazol-2-yl)methyl]-4-phenylpiperidines, is herein disclosed. Structure-activity relationship studies led to potent, selective mGluR2 PAMs with excellent pharmacokinetic profiles. A representative lead compound (+)-17e demonstrated dose-dependent inhibition of methamphetamine-induced hyperactivity and mescaline-induced scratching in mice, providing support for potential efficacy in treating psychosis.
Subject(s)
Antipsychotic Agents/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Imidazoles/chemical synthesis , Piperidines/chemical synthesis , Receptors, Metabotropic Glutamate/metabolism , Allosteric Regulation , Animals , Antipsychotic Agents/pharmacokinetics , Antipsychotic Agents/pharmacology , Biological Availability , Brain/metabolism , Bridged Bicyclo Compounds, Heterocyclic/pharmacokinetics , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Cell Line , Dogs , Humans , Hyperkinesis/chemically induced , Hyperkinesis/drug therapy , Imidazoles/pharmacokinetics , Imidazoles/pharmacology , In Vitro Techniques , Methamphetamine , Mice , Microsomes, Liver/metabolism , Models, Molecular , Piperidines/pharmacokinetics , Piperidines/pharmacology , Protein Conformation , Radioligand Assay , Rats , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The SAR of a series of pyridazinone derived 5-HT(2C) agonists has been explored and resulted in identification of a compound with excellent levels of 5-HT(2C) functional agonism and selectivity over 5-HT(2A) and 5-HT(2B). This compound displayed good in vivo efficacy in pre-clinical models of stress urinary incontinence, despite having physiochemical properties commensurate with impaired CNS penetration.
Subject(s)
Piperazines/chemical synthesis , Pyridazines/chemical synthesis , Serotonin 5-HT2 Receptor Agonists , Serotonin Receptor Agonists/chemical synthesis , Animals , Dogs , Drug Design , Humans , Piperazines/chemistry , Piperazines/pharmacology , Pyridazines/chemistry , Pyridazines/pharmacokinetics , Pyridazines/pharmacology , Receptor, Serotonin, 5-HT2A/metabolism , Receptor, Serotonin, 5-HT2B/metabolism , Receptor, Serotonin, 5-HT2C/metabolism , Serotonin Receptor Agonists/chemistry , Serotonin Receptor Agonists/pharmacokinetics , Structure-Activity Relationship , Urinary Incontinence, Stress/drug therapyABSTRACT
New 7-sulfonamido-3-benzazepines 3 are disclosed as 5-HT(2C) receptor agonists. Appropriate substitution of the amino group (R(1)R(2)N-) gave compounds that were potent 5-HT(2C) agonists with minimal activation of the 5-HT(2A) and 5-HT(2B) receptors. Furthermore, representative examples had excellent in vitro ADME properties and good selectivity over ion channel activity.
