Jutkiewicz Emily M, Eller Erik B, Folk John E, Rice Kenner C, Traynor John R, Woods James H
Department of Pharmacology 1301 MSRB 3, University of Michigan Medical School, Ann Arbor, MI 48109-0632, USA.
J Pharmacol Exp Ther. 2004 Apr;309(1):173-81. doi: 10.1124/jpet.103.061242. Epub 2004 Jan 13.
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.
二芳基哌嗪δ-阿片受体激动剂SNC80 [（+）-4-[（αR）-α-[(2S,5R)-2,5-二甲基-4-(2-丙烯基)-1-哌嗪基]-(3-甲氧基苯基)甲基]-N,N-二乙基苯甲酰胺] 在大鼠中可引发惊厥、产生类抗抑郁作用以及引起运动兴奋。本研究比较了SNC80及其两种衍生物SNC86 [（+）-4-[α(R)-α-[(2S,5R)-2,5-二甲基-4-(2-丙烯基)-1-哌嗪基]-(3-羟基苯基)甲基]-N,N-二乙基苯甲酰胺] 和SNC162 [（+）-4-[（αR）-α-[(2S,5R)-2,5-二甲基-4-(2-丙烯基)-1-哌嗪基]-(3-苯基)甲基]-N,N-二乙基苯甲酰胺] 对Sprague-Dawley大鼠的行为影响，这两种衍生物在苄基环的3位上有一个官能团不同。在行为学检测中，这三种化合物显示出效力和效能的等级顺序；SNC86效力和效能最高，其次是SNC80，然后是SNC162。在体外，通过体外放射自显影法检测发现，这些化合物能刺激未接触过药物大鼠冠状脑片尾状壳核中的鸟苷5'-O-(3-[(35)S]硫代)三磷酸（[(35)S]GTPγS）结合。在[(35)S]GTPγS结合研究中，SNC86似乎是δ-阿片受体的完全激动剂；然而，与SNC86相比，SNC162的刺激作用减弱，这与部分激动剂活性一致。尽管在[(35)S]GTPγS放射自显影研究中SNC80并非完全有效，但它产生的行为效应与SNC86观察到的相似，这表明SNC80的行为效应可能由其3-羟基代谢产物产生。
