Vol. 302, Issue 1, 374-380, July 2002

8-Carboxamidocyclazocine: A Long-Acting, Novel Benzomorphan

Jean M. Bidlack, Dana J. Cohen, Jay P. McLaughlin, Rongliang Lou, Yingchun Ye and Mark P. Wentland

Department of Pharmacology and Physiology, University of Rochester, School of Medicine and Dentistry, Rochester, New York (J.M.B., D.J.C., J.P.M.); and Department of Chemistry, Rensselaer Polytechnic Institute, Troy, New York (R.L., Y.Y., M.P.W.)

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 -receptor, and no change in the affinity for the µ-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-[³⁵S]thio)triphosphate ([³⁵S]GTPS) binding assay, the two compounds produced moderate stimulation of GTP binding to the human - and µ-receptors. When given by i.c.v. injection, the compounds produced less than 60% antinociception in the mouse 55°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 - and µ-opioid receptors. Cyclazocine acted as a µ-antagonist in addition to its agonist properties at the µ-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 µ-opioid receptor antagonist in this assay. An i.p. injection of an ED₇₀ 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.