Synthesis and biological activities of optical isomers of 2-(4-diphenylmethyl-1-piperazinyl)ethyl methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate (manidipine) dihydrochloride.
Enantiomeric (+)- and (-)-manidipine (1) dihydrochlorides were synthesized by the esterification of the optically active monocarboxylic acids (-)-6 and (+)-6, respectively. The absolute configurations, (S)-(+)-1 and (R)-(-)-1, were unambiguously determined by X-ray crystallographic analysis of (+)-7 derived from (-)-6. The (S)-(+)-1 was about 30 and 80 times as potent as the (R)-(-)-isomer in antihypertensive activity in spontaneously hypertensive rats (SHR), and in the radioligand binding assay using [3H]nitrendipine, respectively.
Kajino
M
M
Wada
Y
Y
Nagai
Y
Y
Nagaoka
A
A
Meguro
K
K
D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis*; D055598:Chemical Phenomena; D002621:Chemistry; D004095:Dihydropyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009206:Myocardium / Q000378:metabolism; D009578:Nitrobenzenes; D010879:Piperazines; D051381:Rats; D013237:Stereoisomerism
D000959:Antihypertensive Agents; D004095:Dihydropyridines; D009578:Nitrobenzenes; D010879:Piperazines; C054218:manidipine