Pharmacophore modelling of structurally unusual diltiazem mimics at L-type calcium channels

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.