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

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. MCL-145 [bis(N-cyclobutylmethylmorphinan) fumarate] is related to the morphinan cyclorphan and its N-cyclobutylmethyl derivative MCL-101 [3-hydroxy-N-cyclobutylmethyl morphinan S-( )-mandelate]. MCL-145 consists of two morphinans connected by a spacer at the 3-hydroxy position. This compound had Ki values of 0.078 and 0.20 nM for the and opioid receptors, respectively, using radioligand binding assays as shown by Neumeyer et al. in 2003. In the guanosine 5 -O -(3-[ S]thiotriphosphate) binding assay, MCL145 produced an Emax value of 80% for the opioid receptor and 42% for the opioid receptor. The EC50 values obtained for this compound were 4.3 and 3.1 nM for the and opioid receptors, respectively. In vivo MCL-145 produced a full doseresponse curve in the 55°C warm water tail-flick test and was equipotent to morphine. The agonist properties of MCL-145 were antagonized by the -selective antagonist -funaltrexamine and the -selective antagonist nor-binaltorphimine. MCL145 also acted as a antagonist, as measured by the inhibition of morphine-induced antinociception. 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, 1988, 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 This work was supported by Grants K05-DA00360 and T32 DA07232 (to J.M.B.) and DA014251 (to J.L.N.) from the National Institute on Drug Abuse. Part of this work was presented as a meeting abstract: Mathews JL, Xiong W, Gu X-H, Neumeyer JL, and Bidlack JM (2003) In vivo characterization of MCL-145: a morphinan derivative possessing mixed kappa agonist and mu agonist/antagonist properties, in Abstracts of 34th International Narcotics Research Conference (no. 153), Perpignan, France, July 6–11, 2003; available at http://www.inrcworld.org. Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.105.084343. ABBREVIATIONS: U50,488, (trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide methane-sulfonate hydrate; MCL101, 3-hydroxy-N-cyclobutylmethyl morphinan S-( )-mandelate; Mr2034, ( )-(1R,5R,9R,2 S)-5,9-dimethyl-2 -hydroxy-2-tetrahydrofurfuryl-6,7benzomorphan-D-tartrate; MCL-145, bis(N-cyclobutylmethylmorphinan) fumarate; GTP S, guanosine-5 -O-(3-thio)triphosphate; CHO, Chinese hamster ovary; hKOR, human opioid receptor; hMOR, human opioid receptor; ICI 174,864, N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH (where Aib is -aminoisobutyric acid); -FNA, -funaltrexamine; nor-BNI, nor-binaltorphimine; CL, confidence limits; U69,593, (5 ,7 ,8 )-( )-N-methyl-N-(7(1-pyrrolidinyl)-1-oxaspiro(4,5)dec-8-yl) benzeneacetamide. 0022-3565/05/3152-821–827$20.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 315, No. 2 Copyright © 2005 by The American Society for Pharmacology and Experimental Therapeutics 84343/3056556 JPET 315:821–827, 2005 Printed in U.S.A. 821 at A PE T Jornals on A uust 0, 2017 jpet.asjournals.org D ow nladed from (Schenk et al., 1999, 2000). Although highly selective agonists did have utility for attenuating many cocaine-induced behaviors, these selective agonists produced many severe undesirable side effects. The highly efficacious and selective agonists enadoline, U50,488, and spiradoline produced salivation, emesis, and sedation in nonhuman primates (Negus et al., 1997; Mello and Negus 1998). Bowen et al. (2003) recently reported on a series of compounds with mixed and activity. Included in the report are the morphinans MCL-101 and cyclorphan and the benzomorphan Mr2034. These compounds decreased cocaine self-administration in rhesus monkeys and produced fewer side effects than the -selective agonist enadoline (Bowen et al., 2003). It was also noted that compounds with mixed agonist and agonist activity produced a more sustained decrease in cocaine self-administration than compounds with agonist and antagonist properties (Bowen et al., 2003). Our current data focused on a new compound, MCL-145, which was a mixed agonist and agonist/antagonist. MCL145 is a novel bivalent ligand related to the morphinan ( )-cyclorphan and its N-cyclobutylmethyl derivative MCL101. This compound had high affinity for both the and opioid receptors. The present study characterizes the pharmacological properties of MCL-145 in the [S]GTP S binding assay and in mouse antinociceptive tests. Materials and Methods