ABSTRACT
Ligand-based virtual screening with a 3D pharmacophore led to the discovery of 30 novel, diverse and drug-like ligands of the human cannabinoid receptor 1 (hCB(1)). The pharmacophore was validated with a hit rate of 16%, binding selectivity versus hCB(2), and expected functional profiles. The discovered compounds provide new tools for exploring cannabinoid pharmacology.
Subject(s)
Chemistry, Pharmaceutical/methods , Receptor, Cannabinoid, CB1/metabolism , Receptor, Cannabinoid, CB2/metabolism , Animals , Cannabinoids/chemistry , Cannabis/metabolism , Dose-Response Relationship, Drug , Drug Design , Drug Evaluation, Preclinical , Humans , Ligands , Mice , Models, Chemical , Molecular Structure , Obesity/drug therapy , Piperidines/pharmacology , Pyrazoles/pharmacology , Receptor, Cannabinoid, CB1/chemistry , Receptor, Cannabinoid, CB2/chemistry , RimonabantSubject(s)
Receptor, Serotonin, 5-HT2C/metabolism , Animals , Anti-Obesity Agents/pharmacology , Anti-Obesity Agents/therapeutic use , Antipsychotic Agents/pharmacology , Antipsychotic Agents/therapeutic use , Drug Design , Humans , Ligands , Mental Disorders/drug therapy , Obesity/drug therapy , Serotonin 5-HT2 Receptor Agonists , Serotonin 5-HT2 Receptor Antagonists , Structure-Activity RelationshipABSTRACT
Ligand-based virtual screening led to the discovery of a new class of potent inverse agonists of the human cannabinoid receptor 1, hCB(1), which are selective versus hCB(2). These CB(1) ligands present intriguing departures from a classical CB(1) antagonist pharmacophore. Elements of SAR are discussed in this context.
Subject(s)
Cannabinoids/chemical synthesis , Cannabinoids/pharmacology , Receptor, Cannabinoid, CB1/agonists , Cannabinoids/chemistry , Combinatorial Chemistry Techniques , Drug Design , Humans , Ligands , Molecular Structure , Receptor, Cannabinoid, CB2/agonists , Structure-Activity RelationshipABSTRACT
The camphor-derived tetrahydropyran (camTHP*)-desymmetrized glycinamide 1 undergoes efficient and highly diastereoselective lithium enolate Michael additions to nitro olefins, alpha,beta-unsaturated ketones, esters, and lactones. Straightforward manipulation of these products affords 3-substituted pyroglutamides and beta-aryl-alpha,gamma-diamino acid derivatives, highlighting the ease of synthesis of enantiomerically enriched, functionally dense molecules using this novel building block. [reaction: see text]
Subject(s)
Amino Acids/chemical synthesis , Glycine/analogs & derivatives , Camphor/chemistry , Glycine/chemistry , StereoisomerismABSTRACT
Stereoselective allylation of camphor and subsequent terminal hydroformylation affords a new delta-lactol auxiliary (camTHP*OH) on multigram scale. Stereoselective condensation with glycine dimethylamide and Cbz protection affords a camTHP*-desymmetrized glycinamide building block which undergoes efficient and highly diastereoselective metal enolate alkylation reactions. Acid-mediated deprotection affords the N-Cbz-protected alpha-amino amide products which may be converted directly to alpha-amino ketones on treatment with Grignard or organolithium reagents without loss of stereochemical integrity. [reaction: see text]
