Analgesic and other pharmacological activities of a new narcotic antagonist analgesic (-)-1-(3-methyl-2-butenyl)-4-[2-(3-hydroxyphenyl)-1-phenylethyl]piperazine and its enantiomorph in experimental animals

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Abstract
Of 1-cyclohexyl-4-[2-(3-hydroxyphenyl)-1-phenylethyl]piperazine (I) and its 1-(3-methyl-2-butenyl) derivative (II), the S(+)-isomers were analgesically more active than either their R (-)-isomers or their racemates, having 15 to 44 times the potency of morphine in mice and rats. R (-)-I had comparable analgesic activity to morphine R (-)-II to pentazocine in mice, rats and dogs and they were nearly equipotent with pentazocine in reversing some actions of morphine. The S (+)-isomers and racemates lacked this action. R (-)-II required about 10 times more naloxone to reverse its analgesic activity than was needed to antagonise the S (+)-isomers, morphine and pentazocine. The S (+)-isomers and racemates produce a typical Straub tail reaction and increased spontaneous locomotor activity in mice, but the R (-)-isomers did not. R (-)-II had no significant physical dependence liability in mice, rats and monkeys. From these results, it is suggested that the compounds show an uncommon stereoselectivity in comparison with morphine and its surrogates, and that R (-)-II is worth investigating further as a narcotic antagonist analgesic.