Schetz J A, Calderon S N, Bertha C M, Rice K, Porreca F
Department of Pharmacology, University of Arizona College of Medicine, Tucson, USA.
J Pharmacol Exp Ther. 1996 Dec;279(3):1069-76.
Activation of opioid delta receptors produces antinociception without some of the side-effects associated with activation of mu and kappa receptors. (+/-)-BW373U86 [(+/-)-4-[(alpha-R*)-alpha-((2S*,5R*)-4-allyl-2, 5-dimethyl-1-piperazinyl)-3-hydroxybenzyl]-N,N-diethylbenzamide] is a first generation, racemic nonpeptide, partially delta-selective opioid agonist that produces short-lived antinocioception. After systemic, but not central, administration, (+/-)-BW373U86 is also a naltrindole-reversible convulsant. SNC80 [(+)-4-[9-alpha-R)-alpha-((2S,5RO-4-allyl-2, 5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide] is a chiral methylether derivative of (+/-)-BW373U86 with decreased potency, but greater selectivity for the delta-opioid receptor. Like BW373U86, SNC80 produces brief, nonlethal seizures when administered peripherally, albeit at higher doses. Radiolabeling of SNC80 yields a compound with similar pharmacology named [3H]SNC121. [3H]SNC121 was investigated to determine the relationship between its time course of metabolism and the physiological actions of SNC80. The biotransformation of i.p. administered [3H]SNC121 was established in rats in vivo and in vitro via high-performance liquid chromatography analysis of extracted radioactive tissues and fluids. Radioactive equivalents were characterized by their high-performance liquid chromatography retention times and opioid binding activity in rat brain membranes. The kidney, and especially the liver (within 5 min), rapidly metabolize SNC121 to a metabolite with delta-opioid activity coeluting with BW373U86. Direct i.c.v. administration of [3H]SNC121 resulted in minimal metabolism after 1 hr. We conclude that i.p., but not i.c.v., administered [3H]SNC121 can be metabolized rapidly and substantially by the liver to a BW373U86-like compound. The in vivo time course of metabolism after i.p. administration of [3H]SNC121 is consistent with the duration of SNC80 antinociception, and the rapid formation of a BW373U86-like metabolite may also account, in part, for its convulsant properties.
激活阿片δ受体可产生抗伤害感受作用，且不会出现一些与μ受体和κ受体激活相关的副作用。（±）-BW373U86 [（±）-4- [（α-R*）-α-（（2S*，5R*）-4-烯丙基-2,5-二甲基-1-哌嗪基）-3-羟基苄基]-N，N-二乙基苯甲酰胺]是第一代外消旋非肽类、部分δ选择性阿片激动剂，可产生短暂的抗伤害感受作用。经全身（而非中枢）给药后，（±）-BW373U86还是一种纳曲吲哚可逆性惊厥剂。SNC80 [（+）-4- [9-α-R）-α-（（2S，5R0-4-烯丙基-2,5-二甲基-1-哌嗪基）-3-甲氧基苄基]-N，N-二乙基苯甲酰胺]是（±）-BW373U86的手性甲醚衍生物，效力降低，但对δ阿片受体的选择性更高。与BW373U86一样，SNC80经外周给药时，尽管剂量较高，但也会产生短暂的非致命性惊厥。对SNC80进行放射性标记可得到一种药理学性质相似的化合物，名为[3H]SNC121。对[3H]SNC121进行研究以确定其代谢时间进程与SNC80生理作用之间的关系。通过对提取的放射性组织和液体进行高效液相色谱分析，在大鼠体内和体外确定了腹腔注射[3H]SNC121的生物转化情况。放射性等效物通过其在大鼠脑膜中的高效液相色谱保留时间和阿片结合活性进行表征。肾脏，尤其是肝脏（在5分钟内）可迅速将SNC121代谢为一种具有δ阿片活性的代谢物，该代谢物与BW373U86共洗脱。直接脑室内注射[3H]SNC121在1小时后代谢极少。我们得出结论，腹腔注射而非脑室内注射的[3H]SNC121可被肝脏迅速大量代谢为一种类似BW373U86的化合物。腹腔注射[3H]SNC121后体内的代谢时间进程与SNC80抗伤害感受的持续时间一致，并且类似BW373U86的代谢物的快速形成也可能部分解释了其惊厥特性。
