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BEHAVIORAL PHARMACOLOGY

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

Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan (E.M.J., E.B.E., J.R.T., J.H.W.); and Laboratory of Medicinal Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (J.E.F., K.C.R.)

The diarylpiperazine -opioid agonist SNC80 [(+)-4-[(R)--[(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-[(R)--[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-hydroxyphenyl)methyl]-N,N-diethylbenzamide] and SNC162 [(+)-4-[(R)--[(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]GTPS) binding in the caudate putamen of coronal brain slices from drug-naive rats as measured by in vitro autoradiography. In [³⁵S]GTPS binding studies, SNC86 seemed to be a full agonist at the -opioid receptor; however, SNC162 demonstrated reduced stimulation compared with SNC86, consistent with partial agonist activity. Although SNC80 was not fully efficacious in [³⁵S]GTPS 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.

Address correspondence to: Dr. James H. Woods, 1301 MSRB 3, Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109-0632. E-mail: jhwoods{at}umich.edu

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