5-Selective opioid agonist

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]. 

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. 

Table 3 Effectiveness of a selected experimental agent as an antagonist of [35S]GTP-y-S binding in cloned human opioid receptors stimulated by DAMGO (p,)-, SNS-80 (8)-, and U69,593 (K)-selective opioid agonists...

Taub DD, Eisenstein TK, Geller EB, Adler MW, Rogers TJ (1991) Immunomodulatory activity of X- and K-selective opioid agonists. Proc Natl Acad Sci USA 88 360-364. 

The peptides subtly modified in the side chain at N-terminus residue yielded an opioid with high dual affinities to both 8- and g-opioid receptor types. At present, it appears that the replacement of the Tyr residue by the innatural Dmt analogue in the 5- selective opioid agonist, deltorphin B, produced a peptide with high affinity for both g- and 8-opioid receptors, thereby yielding a 5-opioid receptor ligand which, to all intents and purposes, lacks 5-opioid receptor selectivity. 

Zimmerman DM, Leander JD. Selective opioid receptor agonists and antagonists research tools and potential therapeutic agents. J Med Chem 1990 33 895-902. 

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)... 

It is of historical interest to note that the disclosure of U-50488 occurred at roughly the same time as two chemically unrelated compounds which behave as poorly selective kappa agonist analgesics. These are the benzodiazepine, tifluadom (6) [17] and the amino-terminal nonapeptide fragment of dynorphin, Dyn (1-9), (7) (kappa A) = 0.21 nM, mu K = 3.6 nM delta K, = 3.2 nM) [18], which is thought to be the endogenous kappa opioid agonist. 

Eguchi M. Recent advances in selective opioid receptor agonists and antagonists. Med Res Rev 2004 24 182-212. 

Schwarz RD, Callahan MJ, Davis RE, et al Selective muscarinic agonists for Alzheimer disease treatment, in Alzheimer Disease Therapeutic Strategies. Edited by Giacobini E, Becker R. Boston, MA, Birkhauser, 1994, pp 224-228 Schwarz S, Pohl P Steroids and opioid receptors. J Steroid Biochem Mol Biol 48 391-404, 1994... 

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