3,4-Dimethyl-4-(3-hydroxyphenyl)piperidines: opioid antagonists with potent anorectant activity

Abstract

A series of (3R*,4R*)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine opioid antagonists with varying substituents on the nitrogen were evaluated for their effect on food consumption in obese Zucker rats. Opioid affinity (mu, kappa, and delta for selected compounds) and opioid antagonist activity (mu and kappa) were characterized and compared to effects on food consumption. No compounds with high selectivity for either mu or kappa receptors were discovered. However, compounds in the series had exceptional potency as opioid antagonists and in reducing food consumption in the obese Zucker rat. In contrast, a few compounds with high potency as opioid antagonists had much weaker potency for inhibiting food consumption. (3R,4R)-3,4-Dimethyl-1-[(3S)-3- hydroxy-3-cyclohexyl-propyl]-4-(3-hydroxyphenyl)piperidine (11,LY255582) emerged as having the best activity profile, both in reducing food consumption and as an opioid antagonist. Compound 11 is a highly potent mu, kappa-, and delta-opioid antagonist with possible clinical utility as an appetite suppressant for weight loss.

A Clinical Laboratory Paradigm for Evaluating Medication Effects on Alcohol Consumption: Naltrexone and Nalmefene

“…The results of the present human study suggest that, if there are any differences in opiate receptor binding between naltrexone and nalmefene, these differences do not appear to differentiate clinical response, at least at the doses utilized in this study. The intolerable side effects that occurred in the initial participants who received a faster nalmefene titration (20 mg on the first 2 days) might suggest that either the potency or receptor selectivity of nalmefene is different than naltrexone, as suggested previously (De Haven-Hudkins et al, 1990;Mitch et al, 1993;Emmerson et al, 1994). Alternatively, the recent characterization of nalmefene as an inverse agonist under certain conditions (Wang et al, 2001) suggests that nalmefene, in contrast to naltrexone, might cause an opiate withdrawal-like state under the right conditions.…”

“…There are subtle differences in the receptor pharmacology of these compounds. Both bind strongly to m-opiate receptors in rodent (De Haven-Hudkins et al, 1990;Mitch et al, 1993), and nonhuman primate (Emmerson et al, 1994) brain cortex. However, nalmefene seems to bind more strongly to delta receptors than naltrexone when tested in rodents (De Haven-Hudkins et al, 1990;Mitch et al, 1993) and nonhuman primates (Emmerson et al, 1994).…”

“…Both bind strongly to m-opiate receptors in rodent (De Haven-Hudkins et al, 1990;Mitch et al, 1993), and nonhuman primate (Emmerson et al, 1994) brain cortex. However, nalmefene seems to bind more strongly to delta receptors than naltrexone when tested in rodents (De Haven-Hudkins et al, 1990;Mitch et al, 1993) and nonhuman primates (Emmerson et al, 1994). While in some functional rodent models nalmefene shows greater antagonism for k agonists than naltrexone (CulpepperMorgan et al, 1995), in nonhuman primates (Emmerson et al, 1994) both drugs seem to have similar affinity for k receptors.…”

“…In addition to the primary study goal of evaluating opiate antagonist effects on alcohol consumption in alcoholics and social drinkers, we directly compared the effects of naltrexone and nalmefene on drinking behavior in both natural environment and barlab settings. The primary differences between these two opiate antagonist agents are that nalmefene has a longer half-life and a somewhat different pharmacological profile (eg De Haven-Hudkins et al, 1990;Emmerson et al, 1994;Mitch et al, 1993;Wang et al, 2001). Based on these differences, it was hypothesized that nalmefene might reduce drinking more than naltrexone.…”

Antagonism of opioid receptors reduces body fat in obese rats by decreasing food intake and stimulating lipid utilization

“…Trans-3,4-dimethyl-4-phenylpiperidines are high-affinity non-morphinan opioid receptor antagonists (25,47). Several compounds of this chemical series exhibit subnanomolar in vitro receptor binding and antagonist affinity for the -and -subtypes, with lower affinity for the ␦-receptor (24,25,37).…”