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JA Schetz, SN Calderon, CM Bertha, K Rice and F Porreca
Department of Pharmacology, University of Arizona College of Medicine, Tucson, USA.
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.
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