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Four enantiomers (3a-d) of the title compound, YM-09730 (3), were synthesized by the reaction of (-)- or (+)-5-(methoxycarbonyl)-2, 6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (1a or 1b) with (S)- or (R)-1-benzyl-3-pyrrolidinol (2a or 2b). [3H]Nitrendipine binding affinity and coronary vasodilating activity of these compounds were evaluated. The absolute configuration of the most potent enantiomer (3a) with the longest duration was unequivocally determined to be (S)-1,4-dihydropyridine-C4 and (S)-pyrrolidine-C3 (S,S) by X-ray crystallographic study on 3a X HBr as well as 3a X HCl. The configuration of 1a corresponds to R, and the other enantiomers of 3 were respectively determined by chemical correlation. The potency order of the four enantiomers was (S,S)-3a greater than (S,R)-3b greater than (R,R)-3d greater than (R,S)-3c. Latent chiral characters of nifedipine derivatives with the identical ester groups were assigned by comparison of their puckering modes of 1,4-dihydropyridine (DHP) rings with those found in 3a X HCl or 3a X HBr. On the basis of the assignment, it has been revealed that the (S)-DHP nifedipine derivatives possess the synperiplanar carbonyl group at C5. The conformational restriction may be a factor causing stereoselectivity of antagonism.

Abstract-Effectsof YM-09151-2 and five other neuroleptics (haloperidol, spiperone, chlorpromazine, sulpiride and clozapine) on the binding of [3H]-ligands to nine different receptors (a,-adrenergic, a2-adrenergic, Q-adrenergic, muscarinic, D2-dopaminergic, H1-histaminergic, 5HT,-serotonergic, 5HT2-serotonergic and opiate receptors) and on dopamine-sensitive adenylate cyclase were determined using brain membranes in the rat, guinea-pig and dog. The affinity of YM-091 51-2 for D2-receptors with a K, value of 0.1 nM was more than 1000-times higher than that for the other receptors and dopamine sensitive adenylate cyclase, and it was the greatest among the nueroleptics tested.A close relationship between antidopami nergic and antischizophrenic effects of neu roleptics has been demonstrated by phar macological, electrophysiological, histo chemical and biochemical studies (1). Recent studies have also shown multiplicity of the dopaminergic receptors, referred to as D, (adenylate cyclase-linked), D2 (non adenylate cyclase-linked), D3 (non-adenylate cyclase-linked) and D4 (inversely adenylate cyclase-linked) according to the terminology proposed by Seeman (1, 2), in the brain; and the antischizophrenic effect seems to be at least partly attributable to a blockade of a particular type (D2) of the dopaminergic receptors. However, usefulness of the drugs in the treatment of schizophrenic patients is often limited, partly due to insufficient specificity in the affinity for the D2 dopaminergic receptors, which occasionally results in undesirable side effects such as orthostatic hypotension and thirst. Lack of specificity of neuroleptics for the D2-receptor also makes it difficult to attribute their dopaminergic functions to the D2-receptor.

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