Assessing spiradoline-like discriminative effects of DuP 747: influence of route of administration.
DuP 747, trans-3,4-dichloro-N-methyl-N-[2-(pyrrolidin-1-yl)-1,2,3,4- tetrahydronaphthalen-1-yl]benzeacetamide methanesfonate, is a recently synthesized analgesic drug that binds with high affinity and selectivity to the kappa-opioid receptor. In order to determine if DuP 747 has kappa-like discriminative effects it was tested for stimulus generalization in rats trained to discriminate between SC injections of saline and 3.0 mg/kg of spiradoline, a potent kappa-opioid agonist. A range of drug doses was administered by each of several routes 30 min before a test session. Spiradoline occasioned orderly dose-dependent increases in spiradoline-appropriate lever selection after SC or IP administration, with ED50s of 0.65 and 1.75 mg/kg, respectively. In contrast, DuP 747 (1.0-30 mg/kg) occasioned little spiradoline-appropriate lever selection when administered SC, but was generalized from spiradoline partially when administered IP (ED50 = 5.9 mg/kg) or PO (ED50 = 59 mg/kg). The 5-hydroxy-desmethoxy metabolite of DuP 747, administered SC (0.3-10 mg/kg), occasioned selection of the saline-appropriate lever only. That DuP 747 had little spiradoline-like activity after SC administration suggests that a metabolite of DuP 747 was responsible for the spiradoline-appropriate responding that followed IP and PO administration of the drug, apparently a metabolite other than 5-hydroxy-desmethoxy-DuP 747.
Holtzman
S G
SG
Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322-3090.
Steinfels
G F
GF
Schmidt
W K
WK
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D044482:Benzeneacetamides; D004192:Discrimination, Psychological / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005795:Generalization, Stimulus / Q000187:drug effects; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D007441:Intubation, Gastrointestinal; D008297:Male; D011759:Pyrrolidines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage / Q000494:pharmacology*
D000700:Analgesics; D044482:Benzeneacetamides; D011759:Pyrrolidines; D013764:Tetrahydronaphthalenes; C076987:DuP 747; C087643:3,4-dichloro-N-methyl-N-(2-(pyrrolidin-1-yl)-1,2,3,4-tetrahydro-5-hydroxynaphthalen-1-yl)benzeneacetamide; C051272:spiradoline