ABSTRACT
Novel 4-phenyl-4-[1H-imidazol-2-yl]-piperidine derivatives have been prepared and their synthesis described herein. In vitro affinities for delta-, micro-, and kappa-opioid receptors are reported. Evaluation of some representative compounds from this series in the mouse neonatal ultrasonic vocalization test and the mouse tail suspension test revealed anxiolytic- and antidepressant-like effects, respectively, upon subcutaneous administration.
Subject(s)
Anti-Anxiety Agents/pharmacology , Antidepressive Agents/pharmacology , Piperidines/pharmacology , Receptors, Opioid, delta/agonists , Anti-Anxiety Agents/chemistry , Antidepressive Agents/chemistry , Piperidines/chemistryABSTRACT
A novel series of 4-phenyl-4-[1H-imidazol-2-yl]-piperidine derivatives has been prepared and their synthesis described herein. In vitro affinities for delta-, mu-, and kappa-opioid receptors, as well as the functional activity in the [(35)S]GTPgammaS assay are reported. The most potent and selective delta-opioid agonist 18a exhibited a K(i) of 18 nM, and was >258-fold and 28-fold selective over mu- and kappa-receptors, respectively; the compound is a full agonist with an EC(50) value of 14 nM.
Subject(s)
Drug Industry/methods , Imidazoles/pharmacology , Piperidines/chemistry , Piperidines/pharmacology , Receptors, Opioid, delta/agonists , Binding, Competitive , Drug Design , Imidazoles/chemistry , Kinetics , Models, Chemical , Peptides/chemistry , Structure-Activity RelationshipABSTRACT
Following the program started at Johnson & Johnson Pharmaceutical Research & Development searching for 5-HT(2A/2C) antagonists we now report on the synthesis of a series of substituted 2-(aminomethyl)-3,3a,8,12b-tetrahydro-2H-dibenzocyclohepta[1,2-b]furan derivatives. The 5-HT2A, 5-HT2C and H1 receptor affinities of the described compounds are reported. The mCCP antagonistic activity of a set of selected molecules is also reported.
Subject(s)
Furans/pharmacology , Serotonin 5-HT2 Receptor Antagonists , Serotonin Antagonists/chemical synthesis , Furans/chemical synthesis , Humans , Ligands , Protein Binding , Radioligand Assay , Serotonin Antagonists/pharmacology , Structure-Activity RelationshipABSTRACT
This communication describes the synthesis and in vitro PDE4 inhibitory activity of a novel series of imidazol-2-one and 2-cyanoiminoimidazole derivatives. The compounds described were also tested in in vivo models to evaluate their anti-inflammatory activity after topical administration as well as their gastro-intestinal side effects. Several compounds proved to be potent PDE4 inhibitors and some 2-cyanoiminoimidazoles showed less pronounced gastro-intestinal side effects than reference compounds but maintained anti-inflammatory activity after topical administration.
Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Anti-Inflammatory Agents/chemical synthesis , Imidazoles/pharmacology , Administration, Topical , Animals , Anti-Inflammatory Agents/administration & dosage , Anti-Inflammatory Agents/pharmacology , Cyclic Nucleotide Phosphodiesterases, Type 4 , Disease Models, Animal , Dose-Response Relationship, Drug , Ear Diseases/drug therapy , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Humans , Imidazoles/administration & dosage , Imidazoles/chemical synthesis , Inflammation/drug therapy , Inhibitory Concentration 50 , Rats , Structure-Activity RelationshipABSTRACT
The synthesis of a series of novel 2-(aminoalkyl)-2,3,3a,8-tetrahydrodibenzo[c,f]isoxazolo[2,3-a]azepine derivatives as well as their 5-HT(2A/2C) and H(1) receptor binding affinities are described. The in vivo activity as potential anxiolytics of the synthesised compounds was measured in a mCPP challenge test. One of the compounds, 2a, proved to be a potent 5-HT(2A/2C) receptor antagonist showing as well oral activity and therefore could be considered as a potential anxiolytic/antidepressant agent.
Subject(s)
Azepines/chemical synthesis , Azepines/pharmacology , Receptors, Serotonin/drug effects , Serotonin Antagonists/pharmacology , Animals , Azepines/chemistry , CHO Cells , Cricetinae , Male , Rats , Rats, Wistar , Receptor, Serotonin, 5-HT2A , Receptor, Serotonin, 5-HT2C , Structure-Activity RelationshipABSTRACT
Following the programme started at Janssen Research Foundation searching for 5-HT(2A/2C) antagonists, we now report on the synthesis of a series of substituted 2-(Dimethylaminomethyl)-2,3,3a,8-tetrahydrodibenzo[c,f]isoxazolo[2,3-a]azepine derivatives. The 5-HT(2A), 5-HT(2C) and H(1) receptor affinities as well as the mCPP antagonistic activity of the compounds synthesised is described.