title: Pharmacophore modelling of structurally unusual diltiazem mimics at L-type calcium channels.
abstract: The purpose of this theoretical study was to investigate the molecular features of some structurally unusual calcium antagonists with experimentally proved affinity to the diltiazem-binding site at L-type calcium channels. Therefore, sterical and electronic characteristics of cis-/trans-diclofurime, the verapamil-like derivatives McN-5691 and McN-6186 as well as the natural products papaverine, laudanosine, antioquine and tetrandrine were compared with the pharmacophoric requirements detected for classical diltiazem-like derivatives. This yielded a common pharmacophore model for all of these compounds. Based on this model, one single negative molecular electrostatic potential induced by the free electron pairs of the oxime oxygen of trans-diclofurime was detected that might be responsible for the stronger effects compared to the cis isomer. Furthermore, the dual diltiazem- and verapamil-like features of McN-5691 (and McN-6186) as well as the distinct pharmacophoric assignment of the laudanosine enantiomers may be interpreted on a molecular level. Finally, the crucial partial structure of the bis-benzylisoquinoline derivatives antioquine and tetrandrine being responsible for the calcium antagonistic effects could be revealed by superposition on the most active benzothiazepinone derivative 8-methoxydiltiazem. The results obtained for these unusual diltiazem mimics are discussed taking into consideration earlier findings for classical diltiazem-like derivatives.
authors.affiliation: Heinrich-Heine-Universität Düsseldorf, Institute for Pharmaceutical Chemistry, Germany. kjs@pharm.uni-duesseldorf.de
authors.forename: K J
authors.initials: KJ
authors.lastname: Schleifer
authors.forename: E
authors.initials: E
authors.lastname: Tot
mesh_terms: D004290:DOM 2,5-Dimethoxy-4-Methylamphetamine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002121:Calcium Channel Blockers / Q000737:chemistry* / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000737:chemistry / Q000187:drug effects*; D003198:Computer Simulation; D004110:Diltiazem / Q000031:analogs & derivatives / Q000737:chemistry* / Q000494:pharmacology*; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D008968:Molecular Conformation; D010091:Oximes / Q000737:chemistry / Q000494:pharmacology; D010208:Papaverine / Q000737:chemistry / Q000494:pharmacology; D011437:Propylamines / Q000737:chemistry / Q000494:pharmacology; D055672:Static Electricity
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D007546:Isoquinolines; D010091:Oximes; D011437:Propylamines; C058409:McN 6186; D004290:DOM 2,5-Dimethoxy-4-Methylamphetamine; C055896:McN 5691; C010826:diclofurime; C001522:laudanosine; D010208:Papaverine; D004110:Diltiazem