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Given the mounting evidence for involvement of [delta] opioid receptors in the tolerance and physical dependence of [micro] opioid receptor agonists, we have investigated the possible physical interaction between [micro] and [delta] opioid receptors by using bivalent ligands. Based on reports of suppression of antinociceptive tolerance by the antagonist naltrindole (NTI), bivalent ligands [[micro]-[delta] a gonist-antagonist (MDAN) series] that contain different length spacers, and pharmacophores derived from NTI and the [micro] agonist oxymorphone, have been synthesized and evaluated by intracerebroventricular (i.c.v.) administration in the tail-flick test in mice. In acute i.c.v. studies, the bivalent ligands functioned as agonists with potencies ranging from 1.6- to 45-fold greater than morphine. In contrast, the monovalent [micro] agonist analogues were substantially more potent than the MDAN congeners and were essentially equipotent with one another and oxymorphone. Pretreatment with NTI decreased the E[D.sub.50] values for MDAN-19 to a greater degree than for MDAN-16 but had no effect on MDAN-21. Chronic i.c.v. studies revealed that MDAN ligands whose spacer was 16 atoms or longer produced less dependence than either morphine or [micro] monovalent control MA-19. On the other hand, both physical dependence and tolerance were suppressed at MDAN spacer lengths of 19 atoms or greater. These data suggest that physical interaction between the [micro] and [delta] opioid receptors modulates [micro]-mediated tolerance and dependence. Because MDAN-21 was found to be 50-fold more potent than morphine by the i.v. route (i.v.), it offers a previously uncharacterized approach for the development of analgesics devoid of tolerance and dependence. antinociception | heterodimers

The kinetics of isoindole formation resulting from covalent binding of NNA to wild type and mutant mu opioid receptors were followed in cultured cells using flow cytometry. The finding that NNA bound to mutant mu opioid receptors (K233R and C235s) without producing specific fluorescence enhancement suggested that covalent bonding occurred at these positions to produce an isoindole fluorophore in the wild type mu receptor.

The latest flavoring safety assessments performed by the Expert Panel of the Flavor and Extract Manufacturers Association are presented. A full list of flavorings that are generally recognized as safe is also included.

A unique ketone to allylic alcohol rearrangement has been discovered in the 7-phenylmorphinan-6-one system. The rearrangement is catalyzed by boron tribromide. Its mechanistic pathway is postulated to involve the coordination of the carbonyl group by boron tribromide, which would consequently promote migration of the axial 7-beta-phenyl group.

The Diels-Alder reaction of opiate dienophiles with o-quinodimethanes is a route to tetrahydronaphthalene-fused opiates. This was gleaned from an examination of the Diels-Alder reactions of thebaine and a related opiate with the reactive diene, which led to the synthesis of tetrahydronaphthalene-fused opiates that are not easily available using other means. The 6-methoxy group of thebaine is also found to play a key role in the reaction.

By reacting lithium enolate of hydrocodone with commercially available diphenyliodonium iodide (DII), the conversion of hydrocodone into 7-phenylhydrocodone can be obtained in good amount. The DII approaches the beta-face of the enolate, resulting in enolization and epimerization of the 6-beta isomer, which is then ketonized to the stable 6-alpha epimer.

Selenium group transfer chemistry was used for a stereospecific synthesis of pseudocodeine. The previous approach, wherein codeine is converted to its 6(beta)-chloro derivative and the latter subjected to S(sub N)2 displacemnt in aqueous acetic acid, produces a mixture of isomers where separation of codeine is cumbersome. The stereospecific route involving selenium intermediates proved to have higher yield and better efficiency as it facilitated purification.

MDAN-21, 7'-{2-[(7-{2-[({(5α,6α)-4,5-Epoxy-3,14-dihydroxy-17-methylmorphin-6-yl}-aminocarbonyl)metoxy]-acetylamino} -heptylaminocarbonyl)-methoxy]-acetylamino}-naltrindole, a bivalent opioid ligand containing a mu-opioid receptor agonist (derived from oxymorphone) linked to the delta-opioid receptor antagonist (related to naltrindole) by a spacer of 21 atoms, was reported to have potent analgesic properties in mice. Tolerance, physical dependence, and conditioned place preference were not evident in that species. The finding that bivalent ligands in this series, with spacers 19 atoms or greater, were devoid of tolerance and dependence led to the proposal that MDAN-21 targets heteromeric mu-delta-opioid receptors. The present study focused on its effects in nonhuman primates (Macaca mulatta), a species with a physiology and behavioral repertoire not unlike humans. With regard to opioids, this species usually better predicts clinical outcomes. MDAN-21 substituted for morphine in morphinedependent monkeys in the remarkably low dose range 0.006-0.032 mg/kg, subcutaneously. Although MDAN-21 failed to produce reliable thermal analgesia in the dose range 0.0032-0.032 mg/kg, intramuscularly, it was active in the same dose range and by the same route of administration, in the capsaicin-induced thermal allodynia assay. The results suggest that MDAN-21 may be useful in the treatment of opioid dependence and allodynia. The data provide additional evidence that opioid withdrawal is associated with sensitized pain. [ABSTRACT FROM AUTHOR]

Numerous G protein-coupled receptors (GPCRs) have been shown to form heteromeric receptors in cell-based assays. Among the many heteromers reported in the opioid receptor family are μ/κκ, κ/δ, and μ/δ. However, the in vivo physiological and behavioral relevance for the proposed heteromers have not yet been established. Here we report a unique example of a ligand, N-naphthoyl-β-naltrexamine (NNTA) that selectively activates heteromeric μ/κ-opioid receptors in HEK-293 cells and induces potent antinociception in mice. NNTA was an exceptionally potent agonist in cells expressing μ/κ-opioid receptors. Intriguingly, it was found to be a potent antagonist in cells expressing only μ-receptors. In the mouse tail-flick assay, intrathecal (i.t.) NNTA produced antinociception that was ~100-fold greater than by intracerebroventricular (i.c.v.) administration. The κ-antagonist, norBNI, decreased the i.t. potency, and the activity was virtually abolished in μ-opioid receptor knockout mice. No tolerance was induced i.t., but marginal tolerance (3-fold) was observed via the i.c.v. route. Moreover, NNTA produced neither significant physical dependence nor place preference in the ED50 dose range. Taken together, this work provides an important pharmacologic tool for investigating the in vivo functional relevance of heteromeric μ/κ-opioid receptors and suggests an approach to potent analgesics with fewer deleterious side effects. [ABSTRACT FROM AUTHOR]

Abstract Rationale: Given that alcoholics drink for different reasons, it is not likely that a single pharmacotherapeutic agent will be equally effective for all alcoholics. Hence, the development of new pharmacotherapeutic agents that are capable of reducing alcohol intake remains an important focus in the field of alcohol research. Objective: The objective of the present study was to examine the effects of the delta[sub 2] receptor antagonist naltriben (0.60-4.0 mg/kg) on operant responding maintained by the presentation of ethanol (EtOH) or saccharin in alcohol-preferring (P) rats. Methods: P rats were trained under a concurrent schedule [fixed ratio (FR)4-FR4] to press one lever for EtOH (10% v/v) and another for saccharin (0.0125-0.05% w/v) during a 60-min session. Naloxone, a non-specific opioid receptor antagonist, served as a reference antagonist. Results: When responding maintained by EtOH and saccharin were equated under baseline conditions, naloxone (0.003125-0.75 mg/kg) reduced levels of EtOH-maintained responding by 46-82%. None of the naloxone doses significantly reduced responding maintained by saccharin. Naltriben (0.9-4.0 mg/kg) reduced EtOH-maintained responding by 44-76%, while saccharin-maintained responding was reduced only by the highest dose of naltriben (4.0 mg/kg). Analysis of the EtOH within-session response pattern revealed that naloxone suppressed EtOH-maintained responding during the entire operant session and led to early termination of responding. Low doses of naltriben (0.90 mg/kg and 1.2 mg/kg) suppressed responding during the latter portion of the operant session, while higher doses (2.0, 3.0, 4.0 mg/kg) decreased responding during the entire session and led to early termination of responding. Conclusions: The results of... [ABSTRACT FROM AUTHOR]