Semi-rigid analogues of the calcium antagonist verapamil: A molecular modelling study

Abstract

In this work the rigid-analogue approach has been used to obtain information on the active conformation(s) of the calcium antagonist verapamil. A series of semi-rigid analogues of verapamil were synthesized and their biological activities evaluated on guinea-pig heart and aorta. These molecules were analysed by means of molecular modelling techniques. On the basis of the pharmacological profile and conformational analysis of these compounds, two different models for negative inotropic and negative chronotropic activity are proposed. The two actions seem to be due to conformations of the molecules which differ in the orientation of their phenylethylamino groups.

Design, Synthesis, and Preliminary Pharmacological Evaluation of 4-Aminopiperidine Derivatives as N-Type Calcium Channel Blockers Active on Pain and Neuropathic Pain

“…Chemistry. The reaction pathways used to synthesise the designed compounds (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) are described in Schemes 1-4 and their chemical and physical characteristics are reported in Table 1.…”

“…For several years we have been involved in the design and synthesis of L-type calcium channel antagonists related to verapamil, − and we decided to take advantage of the experience accumulated during this researche to design and study N-type calcium channel antagonists. Indeed, during the past decade, it was found that the classic L-type antagonists are not that specific, as a few of them show some action also on other types of calcium channels, namely the N-type.…”