Clocinnamox mesylate

Pentazocine-induced antinociception is mediated mainly by mu-opioid receptors and compromised by kappa-opioid receptors in mice.[Pubmed:21543510]

J Pharmacol Exp Ther. 2011 Aug;338(2):579-87.

Pentazocine is a widely used mixed agonist-antagonist opioid. Previous animal studies have demonstrated that pentazocine-induced antinociception displayed a ceiling effect characterized by biphasic dose response with a increasing and then descending analgesia like a bell-shaped curve. This study attempted to clarify the mechanisms underlying such dose-response relationships. ddY and C57BL/6J mice received subcutaneous injection of saline or pentazocine (3, 10, 30, 56, or 100 mg . kg(-1)), at 120 min after subcutaneous injection of saline, a mu-opioid receptor antagonist Clocinnamox mesylate (C-CAM) (5 mg . kg(-1)), a kappa-opioid receptor antagonist nor-binaltorphimine (nor-BNI) (10 mg . kg(-1)), or the combination of C-CAM and nor-BNI. The antinociceptive effects of pentazocine were evaluated using tail pressure, hot plate, tail flick, and acetic acid writhing tests. Without pretreatment with an opioid receptor antagonist, the antinociceptive effects of pentazocine exhibited biphasic bell-shaped dose-response curves peaking at 30 mg . kg(-1). C-CAM completely and partly antagonized the antinociception induced by pentazocine at low (3-30 mg . kg(-1)) and high (56-100 mg . kg(-1)) doses, respectively. nor-BNI enhanced the antinociception by pentazocine at high doses and turned the later descending portion of the biphasic dose-response curves into a sigmoid curve. The combination of C-CAM and nor-BNI completely abolished the antinociception by pentazocine at all doses. Our results suggest pentazocine produces antinociception primarily via activation of mu-opioid receptors, but at high doses, this mu-opioid receptor-mediated antinociception is antagonized by concomitant activation of kappa-opioid receptors. This provides the first reasonable hypothesis to explain the ceiling effects of pentazocine analgesia characterized by a biphasic dose response.

Inhibition of morphine tolerance by processed Aconiti tuber is mediated by kappa-opioid receptors.[Pubmed:16446067]

J Ethnopharmacol. 2006 Jun 30;106(2):263-71.

Previously, we found that processed Aconiti tuber (PAT) could inhibit morphine tolerance in mice. In the present study, we investigated mechanisms underlying this effect. Mice received subcutaneous (s.c.) morphine (10 mg/kg) and oral PAT at a subanalgesic dose (0.3 g/kg), once a day for 12 days. Additional PAT-treated groups received morphine and PAT, at 120 min after pretreatment with s.c. Clocinnamox mesylate (C-CAM) (0.5 mg/kg), or nor-binaltorphimine (nor-BNI) (5 mg/kg). The antinociceptive effect was assessed with the tail pressure test, at 60 min after the daily s.c. morphine injections were given. In the placebo-treated group, repeated morphine injections caused morphine tolerance, and morphine antinociception was abolished by day 6, whereas in PAT-treated groups, significant antinociception was maintained until day 12, suggesting that PAT inhibited morphine tolerance, thereby sustaining morphine antinociception. C-CAM, a selective mu-opioid receptor (MOR) antagonist, blocked morphine antinociception whereas nor-BNI, a selective kappa-opioid receptor (KOR) antagonist, did not. However, both C-CAM and nor-BNI could block the antinociception maintained by the morphine-PAT combination. Results of the study suggested that chronic treatment with PAT at a subanalgesic dose maintained MOR-mediated morphine antinociception by attenuating development of morphine tolerance, and that this tolerance-attenuating effect of PAT was mediated by KOR.

Methocinnamox is a potent, long-lasting, and selective antagonist of morphine-mediated antinociception in the mouse: comparison with clocinnamox, beta-funaltrexamine, and beta-chlornaltrexamine.[Pubmed:10945843]

J Pharmacol Exp Ther. 2000 Sep;294(3):933-40.

The irreversible mu-opioid antagonists beta-funaltrexamine (beta-FNA) and beta-chlornaltrexamine (beta-CNA) are important pharmacological tools but have a kappa-agonist activity and, in the latter case, low selectivity. This work examines whether clocinnamox (C-CAM) and the newer analog, methocinnamox (M-CAM), represent improved long-lasting antagonists for examining mu-opioid-mediated effects in vivo. beta-FNA, beta-CNA, C-CAM, and M-CAM were compared after systemic administration in mice and in vitro. beta-FNA and beta-CNA were effective agonists in the writhing assay, reversible by the kappa-antagonist norbinaltorphimine. Neither C-CAM nor M-CAM had agonist activity in vivo. M-CAM was devoid of agonist action at cloned opioid receptors. All four compounds depressed the dose-effect curve for the mu-agonist morphine in the warm-water tail-withdrawal test 1 h after administration; at 48 h, recovery was evident. In the writhing assay, the dose-effect curve for morphine was shifted in a parallel fashion in the order M-CAM >> C-CAM > beta-CNA > or = beta-FNA. In comparison with their ability to shift the dose-effect curve for bremazocine (kappa) and BW373U86 (delta), beta-CNA was the least mu-selective, followed by C-CAM < beta-FNA < M-CAM. M-CAM (1.8 mg/kg) produced a 74-fold increase in the ED(50) of morphine while showing no effect on bremazocine or BW373U86 dose-response curves. In binding assays, C-CAM and M-CAM were 8-fold selective for mu- over kappa-receptors, whereas beta-FNA and beta-CNA were mu/delta-, but not mu/kappa, selective. However, ex vivo binding assays confirmed the mu-receptor selectivity of M-CAM. M-CAM is thus a potent, long-lasting, and specific antagonist at mu-receptors in vivo that lacks confounding agonist actions.

Mechanism of clocinnamox blockade of opioid receptors: evidence from in vitro and ex vivo binding and behavioral assays.[Pubmed:8858971]

J Pharmacol Exp Ther. 1996 Oct;279(1):23-31.

In behavioral experiments, the cinnamoylaminomorphinone clocinnamox (CCAM) has been shown to act as an insurmountable antagonist of mu, but not delta or kappa opioid agonists. In contrast, CCAM displayed only moderate mu selectivity (29:6:1 for mu:delta:kappa) in radioligand displacement experiments using mouse brain membranes. In the present study, the apparent discrepancy between the high mu selectivity of the insurmountable functional antagonism of CCAM and its only moderate mu selectivity in in vitro binding experiments was resolved by in vitro washout experiments and ex vivo binding experiments involving all three opioid receptor types. In the ex vitro washout experiments, CCAM-mediated mu receptor binding inhibition could not be reversed even after allowing for 8 hr hr dissociation, whereas the CCAM inhibition of delta and kappa receptor binding was time-dependently reversed. In the ex vivo binding experiments, 1 hr pretreatment of mice with 10 mg/kg of CCAM i.p. decreased ex vivo [D-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin ([3H]DAMGO) binding (tested at > or = 5 * Kd) by 90%, paralleled by an 88% decrease in mu receptor density in equilibrium saturation binding assays. Ex vivo [3H]DAMGO binding returned to control levels with a T1/2 of 2.7 to 4.2 days (independent of the CCAM dose), the effect being predominantly due to a recovery of mu receptor density. The CCAM inhibition of ex vivo [3H]DAMGO binding was dose-dependent and could be prevented in part by simultaneous administration of the protein synthesis inhibitor cylcoheximide. In contrast to the ex vivo binding of [3H]DAMGO, ex vivo binding of p-[3H]CI-[D-Pen2, D-Pen5]enkephalin or (-)-[3H]bremazocine (in the presence of 1 microM DAMGO and 1 microM [D-Pen6, D-Pen5]enkephalin) was not affected by CCAM pretreatment. Finally, ex vivo [3H]DAMGO binding inhibition data correlated well with mu receptor population changes estimated by Black and Leff analysis of behavioral (antinociception) experiments (T1/2 of receptor reappearance, 3.2 days). Thus, although CCAM reversibly interacted with mu, delta and kappa opioid receptors, only binding to mu receptors was wash-resistant. Binding of methoclocinnamox, a codeinone CCAM precursor with mu agonistic activity, seemed to be at least partially reversible, even at mu receptors.

Irreversible opioid antagonist effects of clocinnamox on opioid analgesia and mu receptor binding in mice.[Pubmed:7965787]

J Pharmacol Exp Ther. 1994 Nov;271(2):715-21.

The effects of the systemically active irreversible opioid receptor antagonist clocinnamox (C-CAM; 14 beta-(p-chlorocinnamoylamino)-7,8-dihydro-N- cyclopropylmethyl normorphinone mesylate) on mu receptor binding to cerebral membranes and on mu opioid analgesia were assessed using mice. After systemic administration, C-CAM produced a dose-dependent decrease in the Bmax values of both [3H]DAMGO ([D-Ala2, N-MePhe4, Gly5-ol][tyrosyl-3,5-3H]enkephalin) and [3H]naltrexone without affecting the Kd value of either ligand. After administration of 3.2 mg/kg of C-CAM, [3H]DAMGO binding recovered gradually, returning to control levels by 8 days. This time course of recovery was similar to that observed with 3.2 mg/kg of C-CAM against morphine analgesia in the warm-water tail-withdrawal assay. The analgesic effect of the mu agonist etonitazene also was assessed in the assay. C-CAM produced dose-dependent rightward and slight downward shifts of the etonitazene dose-effect curve. The analgesic activity of etonitazene had still not returned to base-line levels 12 days after administration of 32 mg/kg of C-CAM, a time at which [3H]DAMGO binding had returned to control levels. In addition, the apparent pA2 values of etonitazene with naltrexone in the tail-withdrawal assay were assessed at 4, 8 and 12 days after the administration of 32 mg/kg of C-CAM, and none were found to be different from the control pA2 value. These results support the notion that C-CAM is an irreversible mu receptor antagonist and suggest that post-treatment, perhaps newly synthesized, mu receptors are similar to mu receptors in control membranes.

Very long-acting narcotic antagonists: the 14 beta-p-substituted cinnamoylaminomorphinones and their partial mu agonist codeinone relatives.[Pubmed:2547389]

Arzneimittelforschung. 1989 May;39(5):570-5.

The biological activity of 14 beta-(p-halo and p-methylcinnamoylamino)-7,8-dihydro-N-cyclopropylmethylnorcodei nones and their corresponding morphinones was investigated. In vitro, the codeinones displayed predominantly mu agonist activity in the 3H-etorphine binding assay and mouse vas deferens preparation. In vivo, in the mouse, the compounds showed weak to inactive antinociception in the tail-flick and hot-plate tets; however, they were potent agonists in the phenylquinone test and moderately weak antagonists in the tail-flick vs morphine test. They also substituted for morphine in withdrawn morphine-dependent rhesus monkeys. When given to non-withdrawn morphine-dependent monkeys, the codeinones precipitated a delayed but long-lasting withdrawal syndrome. They all generalized to codeine in the drug-discrimination test in rhesus monkeys and, in the dose range tested, two compounds were self-administered. This activity is consistent with that of a partial mu agonist. On the other hand, all the morphinones had very long-acting and highly potent mu antagonist properties. The data can be reconciled by assuming that the codeinones are partially metabolized to their respective morphinones. These compounds may be especially useful in the treatment of opioid dependence.