Quinidine as a muscarinic antagonist: a structural approach.

The synthesis, spectroscopic characteristics, and single-crystal X-ray structural analysis of quitenidine methyl ester monohydrate, a derivative of the muscarinic antagonist quinidine, are presented. Quitenidine methyl ester monohydrate (C20H24N2O4.H2O) crystallizes in the orthorhombic space group P2(1)2(1)2(1), with a = 16.69(3) A, b = 12.46(2) A, c = 9.70(1) A, and Z = 4. The crystal structure was refined to a discrepancy factor (R) of 0.097. Substitution of the quinidine vinyl chain with a carboxymethyl group does not influence the conformation. The carboxymethyl group is positionally disordered, a fact that complicates refinement of the structure. The water molecule is bonded to the quinuclidine nitrogen atom, and the hydroxyl group forms an intermolecular hydrogen bond with the quinoline nitrogen atom. The molecular structure of the ester was compared with those of quinidine, quinine, and four other antimuscarinic agents. An approximately linear relationship between the distance from the nonaromatic nitrogen to the plane of the aromatic part of the molecules and the blocking potency of these agents was noted; the greater this distance, the more potent is the antagonist.

Molecular properties of Cinchona alkaloids: a theoretical approach.

In the present work, the conformation analysis, electrostatic potential calculations, and proton affinity evaluation are carried out for Cinchona alkaloids using theoretical molecular mechanics and quantum mechanical methods. The most probable conformation of the active erythro isomers at the receptor site seems to be that which enables the molecule to form intermolecular hydrogen bonds. In epiquinidine, the mutual orientation of O(12) and N(1) atoms favors intra- rather than intermolecular bonding, and this might be responsible for its inactivity. Comparison of the shape and size of the negative electrostatic potential areas provides a tentative explanation for the interaction of different erythro diastereoisomers with the same putative receptor, as well as for lack of such interaction in epiquinidine. The protonation energies calculated for cinchonidine and cinchonine confirm the higher basicity of the aliphatic N(1) as compared with that of the aromatic N(13) atom.