Delta-selective opioid receptor

Spetea, M., Harris, H. E., Berzetei-Gurske, l. P., Klareskog, L., Schmidhammer, H. Binding, pharmacological and immunological profiles of the delta-selective opioid receptor antagonist HS 378, Life Sci. 2001, 69, 1775-1782. 

Portoghese P, Sultana M, Nagase H et al. A highly selective delta-1 opioid receptor antagonist 7-benzylidenenaltrexone. Eur J Pharmacol 1992 218 195-196. 

TABLE 1 Binding Affinities for Selective Opioid Receptor Ligands to Membrane Preparations from COS-7 Cells, Transiently Transfected with the Cloned Human Delta Opioid Receptor... 

Since at the time of the described studies it was thought that the two delta receptor antagonists naltriben (NTB) and 7-benzylidenenaltrexone (BNTX) were selective for the proposed delta-2 and delta-1 receptor subtypes, respectively [19], the relatively high affinity of NTB for the expressed receptors (as compared to BNTX, see Table 1) was thought to be consistent with the cloned human delta receptor being of the delta-2 opioid receptor subtype. 

The clinical evaluation of benzhydrylpiperazines is underway at Ardent Pharmaceuticals, with an injectable mixed delta/mu opioid receptor agonist in trials for the treatment of severe pain. With the development of delta receptor selective opioid agonists with optimized pharmacokinetic properties, other benzhydrylpiperazines (or related agents) are expected to undergo clinical evaluation for the treatment of a variety of indications. Synthetic routes are available to construct these compounds on a reasonable scale and to allow the further development of manufacturing processes. 

The structures of selected peptide and nonpeptide delta-selective opioid antagonists are shown in Figure 1. However, although the compounds shown in Figure 1 have been introduced as neutral delta opioid antagonists, data from more sensitive functional assay systems have subsequently proven that these compounds are also capable of behaving as inverse agonists at the delta opioid receptor under appropriate conditions. 

Three endogenous opioids have been identified enkephalins, dynorphins and beta-endorphins. These opioid peptides selectively bind to the seven transmembrane GPCRs delta (8), kappa (k), and mu (p). Although dynorphin binds predominately to the k receptor, P-endorphines and enkephalins bind to p and 8 opioid receptors. It is important to note that the analgesia induced by opioids is mediated predominately throngh the p opioid receptor. In vitro studies have shown a decrease in the immnne function and proliferation following p-endorphin administration in rodents (Ray and Cohn 1999) and that the immunosuppressive effects by P-endorphins are steroid-independent (Berkenbosch et al. 1984 Nelson et al. 2000). 

Zheng H, Chu J, Qiu Y, Loh HH, Law PY (2008) Agonist-selective signaling is determined by the receptor location within the membrane domains. Proc Natl Acad Sci USA 105 9421-9426 Zhu Y, Hsu MS, Pintar JE (1998) Developmental expression of the mu, kappa, and delta opioid receptor mRNAs in mouse. J Neurosci 18 2538-2549... 

The relative extent of the unwanted effects caused by selective agonists at the different opioid receptors is of great importance in determining if non-mu opioids will have better spectra of actions as compared to morphine. However, there are good indications that the kappa and delta receptor agonists cause less respiratory depression than mu... 

As Shown in table 2, a comparative dose of 10 n units of PCP-like activity inhibited 3H-PCP binding in rat brain membranes, but did not inhibit binding of 3 H - d i hydromorphi ne, 3H - D - a 1 a2 - D -1 eu5-enkephalin, 3H-ethylketocyclazocine, 3H-diazepam, or -neurotensin. These results indicate that the active material is specific and selective from PCP receptors, as binding to the mu, delta, and kappa opioid receptors was unaffected, as was binding to benzodiazepine and neurotensin receptors. 

Page D, McClory A, Mischki T, Schmidt R, Butterworth J, St-Onge S, Labarre M, Payza K, Brown W. Novel Dmt-Tic dipeptide analogues as selective delta-opioid receptor antagonists. Bioorg Med Chem Lett 2000 10 167-170. 

Abdelhamid EE, Sultana M, Portoghese PS, Takemori AE. Selective blockage of delta opioid receptors prevents the development of morphine tolerance and dependence in mice. J Pharmacol Exp Ther 1991 258 299-303. 

Chang KJ, Rigdon GC, Howard JL, McNutt RW. A novel, potent and selective nonpeptidic delta opioid receptor agonist. J Pharmacol Exp Ther 1993 267 852-857. 

Calderon SN, Rothman RB, Porreca F, Flippen-Anderson JL, McNutt RW, Xu H, Smith LE, Bilsky EJ, Davis P, Rice KC. Probes for narcotic receptor mediated phenomena. 19. Synthesis of ( + )-4-[(aR)-a-((25,5R)-4-allyl-2,5-dimethyl-l -piperazinyl)-3-methoxybenzyl]-/V,/V-diethylbenzamide (SNC80) a highly selective, nonpeptide delta opioid receptor agonist. J Med Chem 1994 37 2125-2128. 

Kamei J, Saitoh A, Ohsawa M, Suzuki T, Misawa M, Nagase H, Kasuya Y. Antinociceptive effects of the selective non-peptidic delta-opioid receptor agonist TAN-67 in diabetic mice. Eur J Pharmacol 1995 276 131-135. 

JH. Discriminative stimulus effects of BW373U86 a nonpeptide ligand with selectivity for delta opioid receptors. J Pharmacol Exp Ther 1993 267 888-895. 

Standifer K, Chien C, Wahlstedt C, Brown G, Pasternak G. Selective loss of delta opioid analgesia and binding by antisense oligodeoxynucleotide to a delta opioid receptor. Neuron 1994 12 805-810. 

Human delta opioid receptor Functional studies on stably transfected Chinese hamster ovary cells after acute and chronic treatment with the selective non-peptidic agonist SNC-80. J Pharmacol Exp Ther 1996 278 1083-1089. 

Negus SS, Henriksen SJ, Mattox A, Pasternak GW, Portoghese PS, Takemori AE, Weinger MB, Koob GF. (1993). Effect of antagonists selective for mu, delta, and kappa opioid receptors on the reinforcing effects of heroin in rats. J Pharmacol Exp Ther. 265(3) 1245-52. 

It is now widely accepted that there are at least three opioid receptor sub-types, mu kappa and delta. During the last decade increasing evidence has accumulated to support the hypothesis that a selective kappa opioid agonist will be a powerful analgesic without the clinically limiting side-effects that characterise morphine (e.g., respiratory depression, constipation, addiction)... 

The biochemical and pharmacological properties of the kappa receptor and the differences between the kappa, mu and delta receptors have been reviewed elsewhere. The reader is directed to the opioid review articles by Rees and Hunter (1990) [4], Casy (1989) [3] and Leslie (1987) [10] and also to two shorter reviews which deal specifically with kappa agonists the review by Horwell published in 1988 entitled Kappa Opioid Analgesics [8] and the review by Millan in 1990 on kappa opioid receptors and analgesia [9]. An account of the medicinal chemistry of selective opioid agonists and antagonists was published in 1990 by Zimmerman and Leander [5]. 

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