Calcium Channel Antagonists Discovered by a Multidisciplinary Approach

Abstract

A multidisciplinary project has led to the discovery of novel, structurally diverse, L-type calcium entry blockers (CEBs). The absolute configuration of a recently reported CEB has been determined by vibrational circular dichroism spectroscopy, to assign the stereospecificity of the ligand-channel interaction. Thereafter, a virtual screening procedure was performed with the aim of identifying novel chemotypes for CEBs, starting from a database of purchasable compounds; 340,000 molecules were screened in silico in order to prioritize structures of interest for bioscreening. As a result, 20 compounds were tested in vitro, and functional and binding assays revealed several hits with promising behavior as CEBs.

Synthesis and L-type calcium channel blocking activity of new chiral oxadiazolothiazinones

“…At low concentrations (1e100 nM), compound 2a potentiates the binding of diltiazem, whereas at high concentrations (10e100 mM) diltiazem is displaced [6]. At the cardiovascular level, the oxadiazolothiazinones studied so far are negative inotropic agents, selective for Ca v 1.2 and devoid of vascular effects.…”

“…For some derivatives we separated the racemic mixtures by chiral HPLC, determined their absolute configurations [6e8], and obtained the biological activity of racemates and enantiomers [6,8].…”

Physiological and Pathophysiological Control of Glucagon Secretion by Pancreatic α-Cells

“…L-type channels (long lasting) are composed of the α 1 subunits of the Ca v 1 (Ca v 1.1-1.4) family. They are specifically blocked by dihydropyridines (Carosati et al 2006). P/Q-type channels are composed of the Ca v 2.1 subunit.…”

Determination of the absolute configurations of natural products via density functional theory calculations of vibrational circular dichroism, electronic circular dichroism, and optical rotation: The iso‐schizozygane alkaloids isoschizogaline and isoschizogamine

“…As in prior work, DFT calculations have used the functionals B3LYP and B3PW91 and the basis set TZ2P for IR and VCD calculations [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] and B3LYP and aug-ccpVDZ for ECD and OR calculations. …”