4163-15-9

A series of carbamate analogues were synthesized from levorphanol (1a), cyclorphan (2a) or butorphan (3a) and evaluated in vitro for their binding affinity at μ, δ, and κ opioid receptors. Functional activities of these compounds were measured in the [35S]GTPγS binding assay. Phenyl carbamate derivatives 2d and 3d showed the highest binding affinity for κ receptor (Ki = 0.046 and 0.051 nM) and for μ receptor (Ki = 0.11 and 0.12 nM). Compound 1c showed the highest μ selectivity. The preliminary assay for agonist and antagonist properties of these ligands in stimulating [35S]GTPγS binding mediated by the κ opioid receptor illustrated that all of these ligands were κ agonists. At the μ receptor, compounds 1b, 1c, 2b, and 3b were agonists, while compounds 2c-e and 3c-e were μ agonists/antagonists.

A series of levo- and dextromorphinan pairs have been synthesized and evaluated for their affinities to the mu, kappa, and delta opioid receptors, the N-methyl-d-aspartate (NMDA) channel, and sigma 1 and 2 receptors. It was found that levo isomers tended to have higher affinities at the opioid receptors and moderate to high affinities to the NMDA and sigma receptors, while dextro isomers tended to have lower affinities to the opioid receptors but comparatively higher affinities to the NMDA and sigma receptors. This series of compounds have interesting and complex pharmacological profiles, and merit further investigation as potential therapies for drug abuse treatment.

A series of N-substituted and N′-substituted aminothiazole-derived morphinans (5) were synthesized for expanding the structure-activity relationships of aminothiazolo-morphinans. Although their affinities were somewhat lower thn their prototype aminothiazolo-N-cyclopropylmorphinan (3), 3-aminothiazole derivatives of cyclorphan (1) containing a primary amino group displayed high affinity and selectivity at the κ and μ opioid receptors. [35S]GTPγS binding assays showed that the aminothiazolomorphinans were κ agonists with mixed agonist and antagonist activity at the μ opioid receptor. These novel N′-monosubstituted aminothiazole-derived morphinans may be valuable for the development of drug abuse medications.

Kappa opioid receptors derive their name from the prototype benzomorphan, ketocyclazocine (1a) which was found to produce behavioral effects that were distinct from the behavioral effects of morphine but that were antagonized by the opioid antagonist, naltrexone. Recent evidence suggests that agonists and antagonists at kappa opioid receptors may modulate the activity of dopaminergic neurons and alter the neurochemical and behavioral effects of cocaine. Kappa agonists blocked the effects of cocaine in squirrel monkeys in studies of cocaine discrimination and scheduled-controlled responding. Studies in rhesus monkeys suggested that kappa opioids may antagonize the reinforcing effects of cocaine. These studies prompted the synthesis and evaluation of a series of kappa agonists related to the morphinan, L-cyclorphan (3a) and the benzomorphan, L-cyclazocine (2). We describe the synthesis and preliminary evaluation of a series of morphinans, structural analogs of cyclorphan 3a-c, the 10-keto morphinans 4a and b, and the 8-keto benzomorphan 1b, structurally related to ketocyclazocine (1a). In binding experiments L-cyclorphan (3a), the cyclobutyl (3b), the tetrahydrofurfuryl 3c and the 10-keto 4b analogs had high affinity for mu (μ), delta (δ) and kappa (κ) opioid receptors. Both 3a and 3b were more selective for the κ receptor than the μ receptor. However, 3b was 18-fold more selective for the κ receptor in comparison to the δ receptor, while cyclorphan (3a) had only a 4-fold greater affinity for the κ receptor in comparison to the δ receptor. The cyclobutyl compound 3b was found to have significant μ agonist properties, while 3a was a μ antagonist. All compounds were also examined in the mouse tail flick and writhing assay. Compounds 3a and 3b were κ agonists. Correlating with the binding results, compound 3a had some δ agonist properties, while 3b was devoid of any activity at the δ receptor. In addition, compounds 3a and 3b had opposing properties at the μ opioid receptor. The cyclobutyl compound 3b was found to have significant μ agonist properties, while 3a was a μ antagonist. Copyright (C) 2000 Elsevier Science B.V.

This report concerns the synthesis and preliminary pharmacological evaluation of a novel series of K agonists related to the morphinan (-)- cyclorphan (3a) and the benzomorphan (-)cyclazocine (2) as potential agents for the pharmacotherapy of cocaine abuse. Recent evidence suggests that agonists acting at κ opioid receptors may modulate the activity of dopaminergic neurons and alter the neurochemical and behavioral effects of cocaine. We describe the synthesis and chemical characterization of a series of morphinans 3a-c, structural analogues of cyclorphan [(-)-3-hydroxy-N- cyclopropylmethylmorphinan S(+)-mandelate, 3a], the 10-ketomorphinans 4a,b, and the 8-ketobenzomorphan 1b. Binding experiments demonstrated that the cyclobutyl analogue 3b [(-)-3-hydroxy-N-cyclobutylmethylmorphinan S(+)- mandelate, 3b, MCL-101] of cyclorphan (3a) had a high affinity for μ, δ, and κ opioid receptors in guinea pig brain membranes. Both 3a,b were approximately 2-fold more selective for the κ receptor than for the μ receptor. However 3b (the cyclobutyl analogue) was 18-fold more selective for the κ receptor in comparison to the δ receptor, while cyclorphan (3a) had only 4-fold greater affinity for the κ receptor in comparison to the δ receptor. These findings were confirmed in the antinociceptive tests (tail- flick and acetic acid writhing) in mice, which demonstrated that cyclorphan (3a) produced antinociception that was mediated by the δ receptor while 3b did not produce agonist or antagonist effects at the δ receptor. Both 3a,b had comparable κ agonist properties 3a,b had opposing effects at the μ receptor: 3b was a μ agonist whereas 3a was a μ antagonist.

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