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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

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.

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/κ, 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.

Research in the opioid field has relied heavily on the use of standard agonist ligands such as morphine, [d-Ala(2)-MePhe(4)-Glyol(5)]enkephalin (DAMGO), U69593, bremazocine, [d-Pen(2)d-Pen(5)]enkephalin (DPDPE), and deltorphin-II as tools for investigating the three major types of opioid receptors, MOP (μ), KOP (κ), and DOP (δ), that mediate antinociception. The functional selectivity of these ligands has been based on the assumption that opioid receptors exist as homomers. As numerous studies in cultured cells have suggested that opioid receptors can associate both as homomers and heteromers, we have investigated the selectivity of these standard ligands using intracellular calcium release and [(35)S]GTPγS assays in HEK-293 cells that contain singly and coexpressed opioid receptors. The present study reveals that morphine and DAMGO, traditionally classified as μ selective agonists, selectively activate μ-δ heteromeric opioid receptors with greater efficacy than homomeric opioid receptors. Moreover, standard ligands that have been widely employed as κ- and δ-selective agonists display little or no differences in the activation of homomeric and heteromeric opioid receptors. The far-reaching implications of these results are discussed.

Antinociceptive tail flick responses to heroin and 6-monoacetylmorphine mediated in the brain by mu-opioid receptor are switched by morphine pellet implantation to delta1- and delta2-opioid-receptors mediation, respectively. Present results showed that the mu-receptor response (inhibited by beta-funaltrexamine) to methadone was changed by morphine pellet implantation to delta1 (inhibited by 7-benzylidenenaltrexone)- and delta2 (inhibited by naltriben)-opioid-receptor responses. Methadone pellet implantation likewise changed mediation from mu- to delta-opioid receptors for heroin and methadone but not for morphine (beta-funaltrexamine continued to inhibit). Methadone mu action in the brain was linked through a descending system to activate spinal serotonin receptors (inhibited by methysergide), but this link was gone in the methadone-pellet-implanted group. In the latter group, the new delta1- and delta2-receptor responses were mediated by spinal GABAA (inhibited by bicuculline) and GABAB (inhibited by 2-hydroxysaclofen) receptors. These shifts in neuronal systems meant that mu receptors on a given neuron were not changed into delta receptors. Preliminary results showed that delta-agonist action for methadone was prevented from appearing by MK801, a NMDA-receptor antagonist, and did not occur in 129S6/SvEv mice which lack NMDA responsiveness. Could methadone maintenance treatment in humans uncover delta-agonist actions?