Calcium Entry Blockers and Activators: Conformational and Structural Determinants of Dihydropyrimidine Calcium Channel Modulators

Abstract

Dihydropyrimidines 4, 6, and 15, uniquely designed to unambiguously establish structural and conformational determinants for DHP receptor occupation and for modulation of calcium channel function, were prepared and examined for calcium channel modulation. Our results confirm and firmly establish a preference for syn-orientation of an unsymmetrically substituted aryl moiety at the DHP receptor (15d vs 15e). We propose a normal vs capsized DHP boat model to explain structural and conformational requirements for modulation of calcium channel function that requires an obligatory left-hand side alkoxy cis-carbonyl interaction for maximal DHP receptor affinity, the effect of channel function being determined by orientation of the 4-aryl group. Enantiomers having an up-oriented pseudoaxial aryl group (normal DHP boat) will elicit calcium antagonist activity, whereas enantiomers having a down-oriented pseudoaxial aryl group (capsized DHP boat) will elicit calcium agonist activity. Single enantiomers of macrocyclic lactone 15b demonstrate opposite channel activity. Antagonist activity resides in enantiomer 15b-A (S-configuration, left-hand side alkoxy cis-carbonyl with up-oriented pseudoaxial aryl group and normal DHP boat), whereas agonist activity resides in enantiomer 15b-B (R-configuration, left-hand side alkoxy cis-carbonyl with down-oriented pseudoaxial aryl group and capsized DHP boat). Moreover, this model is consistent with and provides a rational explanation of previous literature in this area, most notably the observation of chiral inversion and potency diminution upon replacement of ester by hydrogen in the Bay K 8644 series.

5-Acetyl-4-(2,5-dimethoxyphenyl)-6-methyl-1-(prop-2-ynyl)-3,4-dihydropyrimidin-2(1H)-one

“…Dihydropyrimidinones (DHPMs) and their derivatives have received much attention because of their biological activities and widespread pharmacological activities, such as antiviral, antibacterial, antitumor and antihypertensive (Rovnyak et al, 1995). Some have been used successfully as calcium channel blockers, 1a-antagonists and neuropeptide Y (NPY) antagonists (Atwal et al, 1990).…”

1-(3-Fluorophenyl)-4,4,6-trimethyl-3,4-dihydropyrimidine-2(1H)-thione

“…For the biological properties of related compounds, see: Rovnyak et al (1995); Kappe (2000); Alam et al (2005); Sriram et al (2006); Leite et al (2006). For related structures, see: Yamin et al (2005); Ismail et al (2007); Saeed et al (2010); Yamin & Salem (2011).…”

“…Pyrimidine-2(1H)-ones/thiones are calcium channel blocker compounds (Rovnyak et al, 1995). They also have other biological activities such as antibacterial, antifungal and antiviral (Kappe, 2000;Alam et al, 2005;Sriram et al, 2006;Leite et al, 2006).…”

A Green Approach for the Synthesis of 2,4-Dihydro-pyrimidinones Using PTSA

“…More recently, they emerged as integral backbones of several calcium channel blockers, antihypertensive agents, α-1a-antagonists, and neuropeptide Y(NPY) antagonists 2 . Dihydropyrimidinone derivatives are found as core units in many marine alkaloids (batzelladine and carambine), which have been found to be potent to HIV-gp-120 CD4 inhibitors 3 .…”