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

Abstract

The diarylpiperazine δ-opioid agonist SNC80 [(+)-4-[(αR)-α-[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-methoxyphenyl)methyl]-N,N-diethylbenzamide] produces convulsions, antidepressant-like effects, and locomotor stimulation in rats. The present study compared the behavioral effects in Sprague-Dawley rats of SNC80 with its two derivatives, SNC86 [(+)-4-[α(R)-α-[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-hydroxyphenyl)methyl]-N,N-diethylbenzamide] and SNC162 [(+)-4-[(αR)-α-[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-phenyl)methyl]-N,N-diethylbenzamide], which differ by one functional group located in the 3-position of the benzylic ring. In behavioral measures, these three compounds demonstrated a rank order of potency and efficacy; SNC86 was the most potent and efficacious followed by SNC80 and then SNC162. In vitro, these compounds stimulated guanosine 5′-O-(3-[³⁵S]thio)triphosphate ([³⁵S]GTPγS) binding in the caudate putamen of coronal brain slices from drug-naive rats as measured by in vitro autoradiography. In [³⁵S]GTPγS binding studies, SNC86 seemed to be a full agonist at the δ-opioid receptor; however, SNC162 demonstrated reduced stimulation compared with SNC86, consistent with partial agonist activity. Although SNC80 was not fully efficacious in [³⁵S]GTPγS autoradiography studies, it produced behavioral effects similar to those observed with SNC86, suggesting that the behavioral effects of SNC80 may be produced by its 3-hydroxy metabolite.