5-Selective opioid peptide

Like morphiceptin and PL017, cisltrans isomerization occurs around the Tyr-Pro amide bond in endomorphin-1, with similar populations (75%trans, 25%cis) found for the two conformations (819). Based on structural comparison of the cis and trans conformations of endomorphin-1 to other /x- and 8-selective opioid peptides, Podlogar et al. proposed that the trans conformation was the bioactive form (819). Recently, Schiller and coworkers reported endomorphin-2 and morphiceptin analogs containing a pseudoproline derivative in... 

While the high affinity for the g-opioid receptor was confirmed in the in vitro pharmacological assay (guinea- pig ileum), in vivo antinociception apparently failed to correlate with high g-opioid receptor activity however, the activity profile of peptide 1 [DMT1] deltorphin B was more closely related to that of the 8- selective opioid peptides 2 (deltorphin B) and 3 (deltorphin C). 

A comprehensive review of receptor selective opioid peptide analogues by Schiller [7] appeared in the previous volume of this Series and for this reason the present chapter describes only non-peptide structures. A leading review which introduces kappa opioid analgesics was written by Horwell in 1988 [8] and a subsequent article focusing on kappa receptors and analgesia by Millan appeared in 1990 [9]. 

Dooley, C. and Houghten, R. (Torrey Pines Institute for Molecular Studies) Novel kappa receptor selective opioid peptides, W09640206 (1996), US5610271 (1997). 

Delta Receptors. There has been considerable interest in 6 opioid agonists because they exhibit antinociceptive effects without the side effects associated with p, opioid receptor agonists. Antinociceptive activity was first demonstrated with 6-selective opioid peptides (see Ref 218 for a review), and more recently with nonpeptidic 6-selective agonists (see Refs. 219-222 for reviews). Of particular interest is the activity of 6 agonists in inflammatory and neuropathic pain (220). Delta opioid receptors also modulate fx opioid receptors and, as discussed earlier, one classification of 6 opioid receptor subtypes was based on their association with p, opioid receptors. There is now considerable evidence that interaction between the two receptor types can alter the activity of p. opioid agonists. Delta agonists... 

Heyl DL, Schullery SE (1997) Developments in the structure-activity relationships for the delta-selective opioid peptides of amphibian skin. Curr Med Chem 4 117-150... 

Schiller, P.W. (1993) Development of receptor-selective opioid peptide analogs as pharmacologic tools and as potential drugs. In Herz, A. (ed.). Handbook of Experimental Pharmacology, vol. 104/1 Opioids I, pp. 681-710. Springer-Verlag, Berlin. 

Structural changes that highly restrict the conformational mobility of the peptides (e.g., substitution of proline for Gly or cyclization of the peptide) have been especially useful for the discovery of receptor-selective opioid peptides. 

Dooley, C.T., Kaplan, R.A., Schiller, P.W, Bidlack, J.M. and Houghten, R.A., Six highly active Mu-selective opioid peptides identified from two synthetic combinatorial libraries. Pep. Res., 3 (1995) 124-137. 

The CCK system shares one property with the opioid system, ie, the existence of selective nonpeptide antagonists. These include aspedicine, a natural benzodiazepine (136), and Devazepide (L-364,718 MK-329) (137). Selective, potent peptide antagonists for CCK, eg, Cl-988 and PD 134308, have been developed that maybe useful as anxiolytics and as dmgs which increase the analgesic effect of morphine but at the same time prevent morphine tolerance (138) (see Hypnotics, sedatives, anticonvulsants, and anxiolytics). 

The opioid peptides vary in their binding affinities for the multiple opioid receptor types. Leu- and Met-enkephalin have a higher affinity for 5-receptors than for the other opioid receptor types (68), whereas the dynorphin peptides have a higher affinity for K-sites (69). P-Endorphin binds with equal affinity to both p- and 5-receptors, but binds with lower affinity to K-sites (70). The existence of a P-endorphin-selective receptor, the S-receptor, has been postulated whether this site is actually a separate P-endorphin-selective receptor or is a subtype of a classical opioid receptor is a matter of controversy (71,72). The existence of opioid receptor subtypes in general is quite controversial although there is some evidence for subtypes of p- (73), 5-(74), and K-receptors (72,75), confirmation of which may be obtained by future molecular cloning studies. 

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). 

Hollt V. Opioid peptide processing and receptor selectivity, Annu Rev Pharmacol Toxicol 1986 26 59-77. 

Hruby VJ, Agnes RS. Conformation-activity relationships of opioid peptides with selective activities at opioid receptors. Biopolymers (Peptide Sci) 1999 51 391-410. 

Wilkes BC, Schiller PW. Theoretical conformational analysis of a p-selective cyclic opioid peptide analog. Biopolymers 1987 26 1431-1444. 

Schiller PW, Weltrowska G, Nguyen TM-D, Lemieux C, Chung NN, Marsden BJ, Wilkes BC. Conformational restriction of the phenylalanine residue in a cyclic opioid peptide analogue effects on receptor selectivity and stereospecificity. J Med Chem 1991 34 3125-3132. 

Corbett AD, Gillan MGC, Kosterlitz HW, McKnight AT, Paterson SJ, Robson LE. Selectivities of opioid peptide analogues as agonists and antagonists at the 6-receptor. Br J Pharmacol 1984 83 271-279. 

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. 

Ni Q., Xu H., Partilla J., Costa B.D., Rice K., Rothman R. Selective labeling of K2 opioid receptors in rat brain by [125I]IOXY interactions of opioid peptides and other drugs with multiple K2a binding sites. Peptides. 14 1279, 1993. 

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. 

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