ABSTRACT
The objective of this study was investigate further the presence of structural or functional analogies between the arylacetamide U50488 [1] and fentanyl [3]. The synthesis and in vitro analgesic activity [hot-plate test] of N-benzyl, N-[2-phenylethyl], and N-[3-phenylpropyl] derivatives of trans-[ +/- ] -N-[2-[1-pyrrolidinyl] cyclohexyl] propanamide [5-7, respectively] were discussed. Attempts to synthesize N-phenyl derivative 4 were also discussed. The lack of significant analgesic activity of 5-7 indicated the stringent structural requirement for the N-methyl-N-arylacetamide group of the k-selective opioid trans-[ +/- ]-2-[3, 4-dichlorophenyl]-N-methyl- N-[2- [1-pyrrolidinyl] cyclohexyl] acetamide [U50488][1]
Subject(s)
Analgesics/chemical synthesis , Acetamides/chemical synthesisABSTRACT
Conjugate addition of pyrrolidine or piperidine to methyl crotonate and hydrolysis of the resulting methyl butyrates gave [ +/- ]-3-pyrrolidino or piperidino-butyric acids [17 and 18, respectively]. Coupling of these racemic acids to aralkylamines, L-phenylalaninamide, or L-phenylalanine methyl ester gave N-substituted butyramides 3-14 which were tested as analgesics using the hot-plate method. [ +/- ]-N-[2-phenethyl]-3-[1-pyrrolidinyl] butyramide [6] showed naloxone-attenuated analgesia but was considerably less potent than morphine and of shorter duration of action. Diastereomeric butyramides containing Phe residue [11-14] were less active analgesic than 6, but unlike N-aralkyl substituted derivatives, showed no toxic effects on locomotor activity at the high doses [30-60 mg/kg] used for testing. In all cases, analgesia was accompanied by inhibition of spontaneous motor activity and sedation