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 κ-receptor, and no change in the affinity for the μ-opioid receptor, with both compounds havingK_i values of less than 1 nM, based on radioligand binding assays. In the guanosine 5′-O-(3-[³⁵S]thio)triphosphate ([³⁵S]GTPγS) binding assay, the two compounds produced moderate stimulation of GTP binding to the human κ- 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 κ- 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.