RAPID IN-VIVO METABOLISM OF A METHYLETHER DERIVATIVE OF (+ -)-BW373U86 - THE METABOLIC-FATE OF [H-3] SNC121 IN RATS/

Activation of opioid delta receptors produces antinociception without some of the side-effects associated with activation of mu and kappa re ceptors. (+/-)-BW373U86 iperazinyl)-3-hydroxybenzyl]-N,N-diethylbenzam ide} is a first generation, racemic nonpeptide, partially delta-select ive opioid agonist that produces short-lived antinocioception. After s ystemic, but not central, administration, (+/-)-BW373U86 is also a nal trindole-reversible convulsant. SNC80 iperazinyl)-3-methoxybenzyl]-N,N -diethylbenzamide} is a chiral methylether derivative of (+/-)-BW373U8 6 with decreased potency, but greater selectivity for the delta-opioid receptor. Like BW373U86, SNC80 produces brief, nonlethal seizures whe n administered peripherally, albeit at higher doses. Radiolabeling of SNC80 yields a compound with similar pharmacology named [H-3]SNC121. [ H-3]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 [H-3]SNC121 was established in rats in vivo and in vitro via high-performance liquid chromatography a nalysis of extracted radioactive tissues and fluids. Radioactive equiv alents were characterized by their high-performance liquid chromatogra phy retention times and opioid binding activity in rat brain membranes . The kidney, and especially the liver (within 5 min), rapidly metabol ize SNC121 to a metabolite with delta-opioid activity coeluting with B W373U86. Direct i.c.v. administration of [H-3]SNC121 resulted in minim al metabolism after 1 hr. We conclude that i.p., but not i.c.v., admin istered [H-3]SNC121 can be metabolized rapidly and substantially by th e liver to a BW373U86-like compound. The in vivo time course of metabo lism after i.p. administration of [H-3]SNC121 is consistent with the d uration of SNC80 antinociception, and the rapid formation of a BW373U8 6-like metabolite may also account, in part, for its convulsant proper ties.