Probes for Narcotic Receptor Mediated Phenomena. 23. Synthesis, Opioid Receptor Binding, and Bioassay of the Highly Selective δ Agonist (+)-4-[(αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]- N,N-diethylbenzamide (SNC 80) and Related Novel Nonpeptide δ Opioid Receptor Ligands

Abstract

The highly selective delta (delta) opioid receptor agonist SNC 80 [(+)-4- [(alpha R)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N ,N- diethylbenzamide, (+)-21] and novel optically pure derivatives were synthesized from the enantiomers of 1-allyl-trans-2,5-dimethylpiperazine (2). The piperazine (+/-)-2 was synthesized, and its enantiomers were obtained on a multigram scale in > 99% optical purity by optical resolution of the racemate with the camphoric acids. The absolute configuration of (+)-2 was determined to be 2S,5R by X-ray analysis of the salt with (+)-camphoric acid. Since the chirality of the starting material was known, and the relative configuration of compounds (-)-21, (-)-22, and (+)-23 were obtained by single-crystal X-ray analysis, the assignment of the absolute stereochemistry of the entire series could be made. Radioreceptor binding studies in rat brain preparations showed that methyl ethers (+)-21 (SNC 80) and (-)-25 exhibited strong selectivity for rat delta receptors with low nanomolar affinity to delta receptors and only micromolar affinity for rat mu (mu) opioid receptors. Compounds (-)-21, (-)-22, and (-)-23 showed micromolar affinities for delta opioid receptors. The unsubstituted derivative (+)-22 and the fluorinated derivative (-)-27 showed > 2659- and > 2105-fold delta/mu binding selectivity, respectively. The latter derivatives are the most selective ligands described in the new series. Studies with some of the compounds described in the isolated mouse vas deferens and guinea pig ileum bioassays revealed that all were agonists with different degrees of selectivity for the delta opioid receptor. These data show that (+)-21 and (+)-22 are potent delta receptor agonists and suggest that these compounds will be valuable tools for further study of the delta opioid receptor at the molecular level, including its function and role in analgesia and drug abuse.

δ-Opioid Agonists: Differential Efficacy and Potency of SNC80, Its 3-OH (SNC86) and 3-Desoxy (SNC162) Derivatives in Sprague-Dawley Rats

“…Although SNC80 produced similar effects to SNC162 in ex vivo studies, this compound was more efficacious in behavioral studies, potentially because it was metabolized to the more active SNC86 product. Consistent with previous in vitro studies (Knapp et al, 1996;Calderon et al, 1997), the present findings confirm that the 3-position of SNC80 alters efficacies and potencies in behavioral studies in Sprague-Dawley rats. In addition, these potency and efficacy differences were observed in the forced swim test, suggesting that this behavioral assay can be used to evaluate and to compare efficacy differences among drugs and possibly drug classes.…”

“…These findings were confirmed in studies in which SNC86 had high affinity for the ␦-opioid receptor (IC 50 ϭ 1.49 nM) in rat brain membranes; but again, this compound was the least selective with a /␦ ratio for inhibition of radioligand ([ ]-enkephalin) binding of 6.5 (Calderon et al, 1997). These studies also demonstrated that SNC80 was less potent (IC 50 ϭ 2.88 nM) but was approximately 130-fold more selective for the ␦-opioid receptor than SNC86.…”

“…SNC162 (IC 50 ϭ 0.94 nM) was the most selective ␦-opioid ligand with a /␦ ratio for inhibition of radioligand binding of greater than 2600. Similarly, in functional assays, SNC162 was approximately 4-fold less potent than SNC80 as determined by inhibition of contraction of electrically stimulated vas deferens of the mouse (Calderon et al, 1997).…”

The selective delta opioid agonist SNC80 enhances amphetamine-mediated efflux of dopamine from rat striatum

“…Some reports indicate peptidic delta agonists elicit dopamine overflow exclusively in the caudate-putamen (Lubetzki et al, 1982;Petit et al, 1986) or the nucleus accumbens (Spanagel et al, 1990;Manzanares et al, 1993), while other reports fail to demonstrate an effect of DPDPE in either area (Mulder et al, 1989;Pentney and Gratton, 1991). These discrepancies could be due to the lack of delta opioid selectivity of DPDPE which produces mu opioid receptor-mediated antinoception in delta opioid knockout mice (Scherrer et al, 2004), whereas SNC80 is greater than 800-fold selective for the delta opioid receptor (Calderon et al, 1997). Indeed, SNC80 failed to induce increases in extracellular dopamine in either the nucleus accumbens or caudate-putamen as measured by in vivo microdialysis at doses that elicited locomotor stimulation and condition placepreference Spina et al, 1998).…”

The δ-Opioid Receptor Agonist SNC80 [(+)-4-[α(R)-α-[(2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl]-(3-methoxybenzyl)-N,N-diethylbenzamide] Synergistically Enhances the Locomotor-Activating Effects of Some Psychomotor Stimulants, but Not Direct Dopamine Agonists, in Rats

“…for peptides and peripheral for nonpeptides) or to the pharmacological differences between ␦-opioid agonists. For example, the nonpeptide SNC80 has a lower K i (approximately 8-fold) for the ␦-opioid receptor and is more efficacious than the peptide DPDPE, even though these compounds have similar selectivities for the ␦-over the -opioid receptor (Calderon et al, 1997;Clark et al, 1997). However, no studies have directly explored these differences in vivo.…”