1. Specific binding of [3H]-prazosin in prostatic and aortic membranes of humans was saturable and of high affinity (prostate: apparent dissociation constant, Kd = 0.35 +/- 0.03 nmol/L; aorta: Kd = 0.26 +/- 0.03 nmol/L). The density of [3H]-prazosin binding sites (Bmax) for prostate and aorta was 546 +/- 31 and 61.6 +/- 1.6 fmol/mg protein, respectively. 2. Prazosin, YM617, naftopidil and urapidil competed with [3H]-prazosin for the binding sites in a dose-dependent manner in the prostate and aorta of humans. The binding affinities of these antagonists in both tissues were compared, based on the inhibition constant, Ki. Both prazosin and urapidil showed similar affinity to [3H]-prazosin binding sites in human tissue, whereas YM617 and naftopidil showed approximately a 12 and two times higher affinity, respectively, to alpha 1-adrenoceptor sites of prostate than aorta. 3. The chloroethylclonidine treatment reduced partially the Bmax values for specific [3H]-prazosin binding in the prostate and aorta of humans with little effect on the Kd values. 4. These data suggest that YM617 is a relatively selective antagonist of human prostatic alpha 1-adrenoceptors.
Methylprednisolone improved the cardiac index, intriguingly, in patients with long term catecholamine treatment in circulatory shock. Myocardial beta-adrenergic receptor also increased in number after the administration of methylprednisolone. However, the hemodynamic improvement caused by methylprednisolone was not observed in patients without beta-adrenergic down-regulation.
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.
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