8-Carboxamidocyclazocine: a long-acting, novel benzomorphan.

Abstract

To obtain benzomorphans with a longer duration of action that may be potential therapeutics for treating cocaine abuse, 8-carboxamidocyclazocine was synthesized. The pharmacological properties of 8-carboxamidocyclazocine were compared with the parent compound cyclazocine. Changing the 8-hydroxyl group on cyclazocine to an 8-carboxamido group resulted in only a 2-fold decrease in the affinity of the compound for the kappa-receptor, and no change in the affinity for the mu-opioid receptor, with both compounds having K(i) values of less than 1 nM, based on radioligand binding assays. In the guanosine 5'-O -(3-[(35)S]thio)triphosphate ([(35)S]GTPgammaS) binding assay, the two compounds produced moderate stimulation of GTP binding to the human kappa- and mu-receptors. When given by i.c.v. injection, the compounds produced less than 60% antinociception in the mouse 55 degrees C warm-water tail-flick test. However, in the mouse writhing test, the compounds had high potency in producing antinociception. Antinociception induced by either 8-carboxamidocyclazocine or cyclazocine was mediated by both kappa- and mu-opioid receptors. Cyclazocine acted as a mu-antagonist in addition to its agonist properties at the mu-receptor, as measured by the inhibition of morphine-induced antinociception. In contrast, 8-carboxamidocyclazocine did not inhibit morphine-induced antinociception, demonstrating that it was not a mu-opioid receptor antagonist in this assay. An i.p. injection of an ED(70) dose of 8-carboxamidocyclazocine produced antinociception that lasted for 15 h in contrast to cyclazocine, which produced antinociception, lasting 2 h. 8-Carboxamidocyclazocine is a novel, long-acting benzomorphan, which possesses pharmacological properties that are distinct from the properties of cyclazocine.

• Authors: Jean M Bidlack, Dana J Cohen, Jay P McLaughlin, Rongliang Lou, Yingchun Ye, Mark P Wentland
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 302 Issue 1 Pg. 374-80 (Jul 2002) ISSN: 0022-3565 [Print] United States
• PMID: 12065740 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 8-carboxamidocyclazocine
• Narcotic Antagonists
• Receptors, Opioid, kappa
• Receptors, Opioid, mu
• Guanosine 5'-O-(3-Thiotriphosphate)
• 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer
• Morphine
• GTP-Binding Proteins
• Cyclazocine

Topics

• 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer (pharmacology)
• Animals
• Brain Chemistry (drug effects)
• Cyclazocine (analogs & derivatives, chemical synthesis, pharmacology)
• Dose-Response Relationship, Drug
• GTP-Binding Proteins (metabolism)
• Guanosine 5'-O-(3-Thiotriphosphate) (metabolism)
• Humans
• Injections, Intraventricular
• Male
• Membranes (drug effects, metabolism)
• Mice
• Mice, Inbred ICR
• Morphine (pharmacology)
• Narcotic Antagonists (pharmacology)
• Pain Measurement (drug effects)
• Receptors, Opioid, kappa (agonists)
• Receptors, Opioid, mu (drug effects)