Opioid agonists delta-receptor selective

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. 

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. 

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Numerous substituents were explored at the para position of this phenyl ring, in search of potent, selective delta opioid receptor agonists. It is important to note at this point that in the 1980s, when much of this work took place, it was often more efficient to test mixtures of stereoisomers to quickly look for potent delta opioid receptor agonists than to separate out the individual isomers (stereoselective routes were eventually developed to reduce the need for difficult separations). For this reason, selectivity data (especially... 

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. 

SELECTIVE DELTA OPIOID RECEPTOR AGONISTS AND THEIR ANTINOCICEPTIVE ACTIONS... 

SNC80 (( +)-4-[(aR)-a-((2S,5R)-4-allyl-2,5-dimethyl-l-piperazinyl)-3-methoxy-benzyl]-N,N-diethylbenzamide), the O-methylated derivative of ( + )-BW373U86,has an affinity of 1 nMfor delta opioid receptors. Moreover, SNC80 has more than 500-fold selectivity for delta versus mu opioid receptors, which is much greater than the receptor selectivity of the parent compound BW373U86 and similar to that of the most selective peptidic delta opioid receptor agonists [40-42]. SNC80 produces weak but replicable antinociceptive effects. 

To further develop delta opioid receptor agonists as potential therapeutics, more compounds should be developed and evaluated in the forced swim test and other models of antidepressant activity. This may allow for the identification of delta opioid agonists with even more selective behavioral effects. Indeed, there are a number of delta opioid agonists with different basic chemical structures that may prove useful. 

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... 

Katsura Y, Zhang X, Homma K et al (1997) Probes for narcotic receptor-mediated phenomena. 25. Synthesis and evaluation of A-alkyl-substituted (a-piperazinylbenzyl)benzamides as novel, highly selective delta opioid receptor agonists. J Med Chem 40 2936-2947... 

Furness SC, Zhang X, Coop A et al (2000) Probes for narcotic receptor-mediated phenomena. 27. Synthesis and pharmacological evaluation of selective delta-opioid receptor agonists from 4-[(aR)-alpha-(2S,5R)-4-substituted-2,5-dimethyl-l-piperazinyl-3-methoxybenzyl]-N, N-diethylbenzamides and their enantiomers. J Med Chem 43 3193-3196... 

Pobleck N, Delorme D, Wei Z-Y et al (2000) New diarylmethylpiperazines as potent and selective nonpeptidic delta opioid receptor agonists with increased in vitro metabolic stability. J Med Chem 43 3878-3894... 

Wei Z-Y, Brown W, Takasaki B et al (2000) N,N-Diethyl-4-(phenylpiperidin-4-ylidene-methyl)benzamide a novel, exceptionally selective, potent delta opioid receptor agonist with oral bioavailability and its analogues. J Med Chem 43 3895-3905... 

K. and Yamamura, H.I. (1983) Conformationally constrained cyclic enkephalin analogs with pronounced delta opioid receptor agonist selectivity. Life Sci. 32 2565-2569. 

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