Rational drug design and synthesis of a selective opioid receptor antagonist on the basis of the accessory site concept.
To newly synthesize a selective opioid receptor antagonist, 17-(cyclopropylmethyl)-4,5 alpha-epoxy-6 beta,21-epoxymethano-3-hydroxy-6,14-endoethenomorphinan-7 alpha-(N-phenethyl)carboxamide was first designed from an opioid receptor agonist TAN-821 on the basis of the accessory site concept. The designed compound antagonized the agonistic effects induced by an opioid receptor agonist beta-endorphin on the rat vas deference test. Moreover, the designed compound blocked the antinociception induced by beta-endorphin given intracerebroventricularly.
Fujii
Hideaki
H
Pharmaceutical Research Laboratories, Toray Industries, Inc., 1111, Tebiro, Kamakura Kanagawa 248-8555, Japan. hideaki_fujii@nts.toray.co.jp
Narita
Minoru
M
Mizoguchi
Hirokazu
H
Hirokawa
Junichi
J
Kawai
Koji
K
Tanaka
Toshiaki
T
Tseng
Leon F
LF
Nagase
Hiroshi
H
D000818:Animals; D015195:Drug Design; D008297:Male; D009019:Morphinans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009292:Narcotic Antagonists; D051381:Rats; D011957:Receptors, Opioid; D014649:Vas Deferens / Q000187:drug effects; D001615:beta-Endorphin / Q000494:pharmacology
C496610:17-(cyclopropylmethyl)-4,5 alpha-epoxy-6 beta,21-epoxymethano-3-hydroxy-6,14-endoethenomorphinan-7 alpha-(N-phenethyl)carboxamide; D009019:Morphinans; D009292:Narcotic Antagonists; D011957:Receptors, Opioid; C043460:epsilon receptor; D001615:beta-Endorphin