Resolution, absolute stereochemistry, and enantioselective activity of nomifensine and hexahydro-1H-indeno[1,2-b]pyridines.
Nomifensine and three selected compounds from the series of H4a,H5-trans,H4a,H9b-cis-2,3,4,4a,5,9b-hexahydro-1H-in deno[1,2-b]pyridines have been resolved into their enantiomers. All compounds exhibit pronounced enantioselective activity with respect to their inhibition of tetrabenazine-induced ptosis and potentiation of yohimbine toxicity. Nomifensine exhibits the same preference for one enantiomer with respect to dopamine and norepinephrine reuptake, whereas in the indeno[1,2-b]pyridine series in vitro experiments do not discriminate between the optical antipodes. The absolute stereochemistry of the pharmacologically active enantiomers in both series was determined by X-ray analyses and comparative CD spectra. For biological activity the diphenylmethane is an essential structure feature in both series. Its absolute configuration proved to be 4S for nomifensine and 5S for indenopyridines. The similar pharmacological profile of the two chemical entities is therefore reflected in an identical configuration of this pharmacologically important molecular part.
D000818:Animals; D001763:Blepharoptosis / Q000139:chemically induced / Q000517:prevention & control; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D004298:Dopamine / Q000378:metabolism; D004357:Drug Synergism; D007189:Indans / Q000138:chemical synthesis / Q000494:pharmacology*; D007192:Indenes / Q000494:pharmacology*; D007536:Isomerism; D008297:Male; D051379:Mice; D008968:Molecular Conformation; D009627:Nomifensine / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism; D010880:Piperidines / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D012701:Serotonin / Q000378:metabolism; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000378:metabolism; D013747:Tetrabenazine; D015016:Yohimbine / Q000633:toxicity
D007189:Indans; D007192:Indenes; D010880:Piperidines; C052346:1-methyl-5-phenyl-2,3,4,4a,5,9b-hexahydro-1H-indeno(1,2-b)pyridine; C052347:1-propyl-5-phenyl-2,3,4,4a,5,9b-hexahydro-1H-indeno(1,2-b)pyridine; C052348:5-(4-aminophenyl)-2,3,4,4a,5,9b-hexahydro-1H-indeno(1,2-b)pyridine; D009627:Nomifensine; D015016:Yohimbine; D012701:Serotonin; D004298:Dopamine; D009638:Norepinephrine; D013747:Tetrabenazine