title: Delta-opioid agonists: differential efficacy and potency of SNC80, its 3-OH (SNC86) and 3-desoxy (SNC162) derivatives in Sprague-Dawley rats.
abstract: The diarylpiperazine delta-opioid agonist SNC80 [(+)-4-[(alphaR)-alpha-[(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-[alpha(R)-alpha-[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-hydroxyphenyl)methyl]-N,N-diethylbenzamide] and SNC162 [(+)-4-[(alphaR)-alpha-[(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-[(35)S]thio)triphosphate ([(35)S]GTPgammaS) binding in the caudate putamen of coronal brain slices from drug-naive rats as measured by in vitro autoradiography. In [(35)S]GTPgammaS binding studies, SNC86 seemed to be a full agonist at the delta-opioid receptor; however, SNC162 demonstrated reduced stimulation compared with SNC86, consistent with partial agonist activity. Although SNC80 was not fully efficacious in [(35)S]GTPgammaS 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.
authors.affiliation: Department of Pharmacology 1301 MSRB 3, University of Michigan Medical School, Ann Arbor, MI 48109-0632, USA.
authors.forename: Emily M
authors.initials: EM
authors.lastname: Jutkiewicz
authors.forename: Erik B
authors.initials: EB
authors.lastname: Eller
authors.forename: John E
authors.initials: JE
authors.lastname: Folk
authors.forename: Kenner C
authors.initials: KC
authors.lastname: Rice
authors.forename: John R
authors.initials: JR
authors.lastname: Traynor
authors.forename: James H
authors.initials: JH
authors.lastname: Woods
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000378:metabolism*; D013644:Tartrates / Q000494:pharmacology*
chemical_list: C484285:((+)-4-((alphaR)-alpha-((2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl)-(3-phenyl)methyl)-N,N-diethylbenzamide); D001549:Benzamides; D010879:Piperazines; D017465:Receptors, Opioid, delta; D013644:Tartrates; C088464:4-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C435201:2,3-bis(benzoyloxy)tartaric acid