Morphinans

Abstract: A novel series of morphinans were synthesized, and their binding affinity at and functional selectivity for micro, delta, and kappa opioid receptors were evaluated. These dimeric ligands can be viewed as dimeric morphinans, which were formed by coupling two identical morphinan pharmacophores (cyclorphan (1) or MCL 101 (2)) with varying connecting spacers. Ligands 6 and 7 with alkyl spacers on the nitrogen position and ligands 8 and 9 in which the two morphinan pharmacophores were coupled by ether moieties at the 3-hydroxyl positions showed significant decrease in affinity at all three opioid receptors. An improvement in the affinity was achieved by introducing an ester moiety as the spacer in the dimeric morphinans. It was observed that the affinity of these ligands was sensitive to the character and length of the spacer. Compound 13 (MCL-139) with a 4-carbon ester spacer, compound 17 (MCL-144) containing a 10-carbon spacer, and compound 19 (MCL-145) with the conformationally constrained fumaryl spacer were the most potent ligands in this series, displaying excellent affinities at micro and kappa receptors (K(i) = 0.09-0.2 nM at micro and K(i) = 0.078-0.049 nM at kappa), which were comparable to the parent compound 2. Ligand 12, a compound containing only one morphinan pharmacophore and a long-chain ester group, had affinity at both micro and kappa receptors almost identical to that of the parent ligand 2. In the [(35)S]GTPgammaS binding assay, ligands 13, 17, and 19 and their parent morphinans 1 and 2 stimulated [(35)S]GTPgammaS binding mediated by the micro and kappa receptors. Compounds 13 and 17 were full kappa agonists and partial micro agonists, while compound 19 was a partial agonist at both micro and kappa receptors. These novel ligands, as well as their interesting pharmacological properties, will serve as the basis for our continuing investigation of the dimeric ligands as potential probes for the pharmacotherapy of cocaine abuse and may also open new avenues for the characterization of opioid receptors.

Abstract: GPA‐1657, profadol, and propiram are proposed as analgesies of low abuse potential since none will suppress but each will precipitate abstinence in morphine‐dependent monkeys. GPA‐1657 is not an antagonist in man but a typical morphine‐like compound and is fudged to have significant abuse potential. Profadol and propiram act as antagonists in man and precipitate abstinence in subiects dependent on 240 mg. of morphine per day. As agonists, profadol and propiram resemble morphine‐like rather than nalorphine‐like drugs, since both produce morphine‐like subjective effects and physical dependence and suppress abstinence in subiects dependent on 60 mg. per day of morphine. Both were judged to have abuse potential. Propiram was judged to have somewhat less abuse potential than profadol, since it produces less euphoria and less physical dependence. The morphine antagonist properties of profadol and propiram are thought to be caused by the fact that they are morphine agonists with less intrinsic activity than morphine.