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 havingKi 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.
Footnotes
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This work was supported by Grants K05-DA00360, DA-03742, and DA-12180 from the National Institute on Drug Abuse.
- Abbreviations:
- EKC
- ethylketocyclazocine
- U50,488
- (trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide methane-sulfonate hydrate
- CHO
- Chinese hamster ovary
- GTPγS
- guanosine-5′-O-(3-thio)triphosphate
- 8-CAC
- 8-carboxamidocyclazocine
- DAMGO
- [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin
- U69,593
- (5α,7α,8β)-(−)-N-methyl-N-(7-(1-pyrrolidinyl)-1-oxaspiro(4,5)dec-8-yl) benzeneacetamide
- nor-BNI
- nor-binaltorphimine
- ICI 174,864
- N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH (where Aib is α-aminoisobutyric acid)
- β-FNA
- β-funaltrexamine
- CL
- confidence limit
- Received January 15, 2002.
- Accepted March 15, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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