Structural Basis of the Modulation of the Voltage‐Gated Calcium Ion Channel Ca_v1.1 by Dihydropyridine Compounds**

Abstract

1,4‐Dihydropyridines (DHP), the most commonly used antihypertensives, function by inhibiting the L‐type voltage‐gated Ca2+ (Cav) channels. DHP compounds exhibit chirality‐specific antagonistic or agonistic effects. The structure of rabbit Cav1.1 bound to an achiral drug nifedipine reveals the general binding mode for DHP drugs, but the molecular basis for chiral specificity remained elusive. Herein, we report five cryo‐EM structures of nanodisc‐embedded Cav1.1 in the presence of the bestselling drug amlodipine, a DHP antagonist (R)‐(+)‐Bay K8644, and a titration of its agonistic enantiomer (S)‐(−)‐Bay K8644 at resolutions of 2.9–3.4 Å. The amlodipine‐bound structure reveals the molecular basis for the high efficacy of the drug. All structures with the addition of the Bay K8644 enantiomers exhibit similar inactivated conformations, suggesting that (S)‐(−)‐Bay K8644, when acting as an agonist, is insufficient to lock the activated state of the channel for a prolonged duration.

6-Amino-3-Methyl-4-(2-nitrophenyl)-1,4-Dihydropyrano[2,3-c]Pyrazole-5-Carbonitrile Shows Antihypertensive and Vasorelaxant Action via Calcium Channel Blockade

“…3b, compound 1 (55 and 98 μM) significantly reduced contraction induced by CaCl 2 in a concentration-dependent manner causing that, at the concentration of 98 μM, contraction was totally abolished. This supports the concept that test sample 1 possesses Ca 2 + entry-blocking activity, since it was developed and synthesized as isosteric derivative of dihydropyridines (DHP) such as nifedipine [4,21,23], a potent calcium channel blocker, which is widely used as an antihypertensive agent [24]. Finally, a third experiment was conducted to clearly establish the functional mechanism of action of 1, which consisted in the use of a direct L-type calcium channel agonist, FPL-64176 (FPL).…”

Thermodynamics of the elementary steps of organic hydride chemistry determined in acetonitrile and their applications

“…•+ ) and ΔH PD (DH [60][61][62][63] and great reduction ability. 24,25 Given that our research interest has been focused on exploring the thermodynamic driving forces on each elementary step of organic hydride compounds releasing hydride, in 2018, we successfully synthesized 23 3,5-disubstituted-1,4-dihydropyridines (denoted as OH 2 here for clarity) with diverse electron-withdrawing groups at the 3,5position and N 1 -position (Scheme 9), 39 and established 23 "Molecule ID Cards" of OH 2 to quantitatively scale the ) hydride-, hydrogen-, proton-, and electron-donating abilities of OH 2 and its reaction active intermediates in acetonitrile to be used to accurately deduce the reduction mechanism.…”

Structures of the R-type human Cav2.3 channel reveal conformational crosstalk of the intracellular segments

“…An unexpected discovery is the conformational flexibility of the AID. In all the reported structures of Ca v 1.1, Ca v 1.3, and Ca v 2.2 8,9,11,12,19,33,34 , AID is a transverse helix lying on the intracellular surface of the membrane, connected to S6 I through a short turn. 3DVA of the low pass-filtered map of ΔCH2 reveals a potentially straightened conformation of the AID as a natural extension of S6 I into the cytosol.…”