Calciseptine is a natural peptide consisting of 60 amino acids with four disulfide bonds. The peptide is a natural L-type Ca2+-channel blocker in heart and other systems, but its actions in skeletal muscle have not been previously described. The aim of this study is to characterize the effects of calciseptine on L-type Ca2+ channels of skeletal muscle and on contraction. Whole-cell, patch-clamp experiments were performed to record Ca2+ currents (I(Ca)) from mouse myotubes, whereas Vaseline-gap voltage-clamp experiments were carried out to record I(Ca) from frog skeletal muscle fibers. We found that calciseptine acts as a channel agonist in skeletal muscle, increasing peak I(Ca) by 37% and 49% in these two preparations. Likewise, the peptide increased intramembrane charge movement, though it had little effect on contraction. The molecular analysis of the peptide indicated the presence of a local, electrostatic potential that resembles that of the 1,4-dihydropyridine agonist Bay K 8644. These observations suggest that calciseptine shares the properties of 1,4-dihydropyridine derivatives in modulating the permeation of divalent cations through L-type channels.
Herein we describe a Free-Wilson/Fujita-Ban QSAR (quantitative structure-activity relationship) analysis of the analgesic potency of over 50 semisynthetic opioid narcotics. The 3-hydroxy- and 3-methoxy-N-alkylmorphinan-6-ones of B/C-cis and -trans stereochemistry include compounds exhibiting structural variation at five positions [N-methyl (C17), oxygen at C3, C4-C5 oxygen bridge, alkyl substituents at C7 and C8]. The pharmacological parameter correlated was the analgesic potency (-log ED50) exhibited on abdominal contractions produced by acetylcholine injection in mice. A satisfactory correlation was obtained only by assuming interdependent contributions of the substituents on C17 and O(C3), with which it was possible to explain 75% of the variance. Phenolic compounds (3-OH) behave somewhat differently from the methyl ethers (3-OCH3), and in both series the substituents on C8 have a size-dependent negative contribution, implying steric hindrance at their contact point on the receptor. With use of this correlation the potency of five further members of the series was predicted. Subsequent testing fully confirmed the validity of the correlation since the measured potencies were, within experimental error, equal to those calculated. In a further refinement, phenolic compounds were considered separately from the ethers, and it was found that the contribution of the substituents on C17, C7, and C8 remained similar in sign and magnitude but not that of the furan oxygen. This analysis allows us to conclude that if both phenolic and nonphenolic members of this series act on the same receptor they must bind at different subsites or in alternate modes, supporting an earlier proposal in the literature.
Fourteen dimethyl 4-aryl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylates (DHPs) were evaluated by means of single crystal X-ray diffraction in order to investigate the effects of the structure in the crystals on the solid state 13C NMR chemical shifts. These include the analysis of three DHPs containing two molecules per asymmetric unit. The chiral rotamer unit generated by the s-cis/s-trans orientation of the carbonyl groups, as well as by rotation of the 4-phenyl ring out of the bisecting plane containing the N1, C4, C7 atoms, resulted in a significant magnetic non-equivalence for the C2-CH3/C6-CH3 and the COOCH3 pairs of signals. The solid state 13C NMR data reveal that the substitution pattern of the phenyl ring has a marked effect on the extent to which the signals of the carbonyl carbon atoms and those of C-2/C-6 peaks are split.
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