Characterization of a Novel Bivalent Morphinan Possessing κ Agonist and μ Agonist/Antagonist Properties

Abstract

Previous research has shown that compounds with mixed and activity may have utility for the treatment of cocaine abuse and dependence. The present study characterizes the pharmacological profile of a bivalent morphinan that was shown to be a opioid receptor agonist and a opioid receptor agonist/antagonist. Research over the past several years has demonstrated the utility of using opioid receptor agonists as part of the continuing search for viable treatment options for cocaine abuse. Agonists and antagonists are known to inhibit dopamine release in the nucleus accumbens (Maissoneuve et al., 1994), a region of the brain that has high levels of opioid receptors (Mansour et al., 1987(Mansour et al., , 1988(Mansour et al., , 1994 and the endogenous opioid peptide dynorphin (Chavkin et al., 1982;Hokfelt et al., 1984). Agonists have also been shown to decrease striatal dopamine levels in rats, whereas cocaine and opioid receptor agonists increase dopamine levels (DiChiara and Imperato, 1988;Spanagel et al., 1992;Devine et al., 1993). Based on the knowledge that agonists and antagonists modulate dopamine levels, Archer et al. (1996) postulated that compounds with mixed and opioid activity may have particular utility in the development of potential pharmacotherapeutic options for the treatment of cocaine abuse.Early research in both nonhuman primates and rats showed that agonists could functionally antagonize many cocaine-induced behaviors, including hyperactivity (Ukai et al., 1994;Crawford et al., 1995), place preference (Suzuki et al., 1992;Crawford et al., 1995;Shippenberg et al., 1996), self-administration (Glick et al., 1995;Negus et al., 1997;Mello and Negus, 1998), and sensitization to hyperactivity and stereotypies (Shippenberg et al., 1996). Administration of agonists also attenuated the reinstatement of extinguished drug-taking behavior, in an animal model of relapse

Pharmacological Characterization of ATPM [(-)-3-Aminothiazolo[5,4-b]-N-cyclopropylmethylmorphinan hydrochloride], a Novel Mixed κ-Agonist and μ-Agonist/-Antagonist That Attenuates Morphine Antinociceptive Tolerance and Heroin Self-Administration Behavior

“…The antinociception produced by ATPM was blocked by both -and -antagonists, indicating that the antinociceptive effects of ATPM are mediated by both -and -receptors, which is consistent with the results observed from other morphinan analogs whose antinociceptive effects were also confirmed to be induced by the mixed -and -agonists (Mathews et al, 2005). In addition to its agonist profile on the -receptor, ATPM also acted as a -antagonist, as measured by its inhibition of morphineinduced antinociception at low doses, similar to its parental compound cyclorphan (Neumeyer et al, 2000a(Neumeyer et al, ,b, 2001).…”

In Vivo Characterization of (−)(−)MCL-144 and (+)(−)MCL-193: Isomeric, Bivalent Ligands with Mu/Kappa Agonist Properties

“…In both radioligand binding and [ 35 S]GTPγS assays, (−)(−)MCL-145 displayed virtually identical pharmacological properties to (−)MCL-101 (1,2) (Tables 1-3). In vivo, (−)(−)MCL-145 was a κ agonist and μ partial agonist, similar to (−)MCL-101 (1,12).…”

“…Within the bivalent ligand series, we previously reported on (−)(−)MCL-145, a bivalent compound with two (−)MCL-101 pharmacophores bridged by a conformationally constrained fumaryl ester (2,12) (Fig. 1).…”

[6,7]‐Heterocycle‐Fused 14‐Hydroxymorphinan Derivatives: Design, Synthesis, and Opioid Receptor Activity

“…As has been reported [8][9][10][11][12][27][28][29] by several research groups, including ours, that k agonists with m partial agonistic or antagonistic activities are more efficacious than the pure k agonists in treating several CNS disorders, especially drug abuse, several compounds in our current studies, such as thiazole 8 and imidazo[2,1-b]thiazoles 10 and 11, which have agonistic activity at the k and partial agonistic or antagonistic activities at m receptors, are worthy of further investigation.…”

“…As we are interested in compounds with k-agonistic and mpartial agonistic or antagonistic activities, [8,9] the k and m receptor double binders 8, 10, and 11 were selected for stimulation or inhibition of [ 35 S]GTPgS binding studies to determine their agonistic or antagonistic functions at these two receptors. As shown in Table 2, thiazole-derived 14-hydroxymorphinan 8, which binds k and m receptors with equipotent affinity, displayed no agonistic stimulation (NS) at the m receptor, whereas partial agonistic activity (E max = 80.7 %) was observed at the k receptor.…”