This paper describes the synthesis, structure-activity relationships (SAR) of mu and kappa opioid binding affinities, and analgesic properties of a series of novel highly selective kappa opioid N-[(2-aminocyclohexyl)aryl]acetamide and N-[(2-aminocyclohexyl)aryloxy] acetamide derivatives. Ten compounds, 14, 15, 31-37, and 39 (Tables I and II), show a marked kappa selectivity of greater than 100:1 over mu binding, with high affinity for the kappa opioid receptor (approximately 10(-8) - 10(-9) M). Compound 39, (S,S-trans)-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-4-benzo[b] furanacetamide hydrobromide, has the highest mu/kappa selectivity, 780:1 (kappa Ki = 4.2 nM), reported to date. Four of these compounds, 14, 15, and their S,S-trans enantiomers, 37 and 39, respectively, produce effective analgesia by oral administration, as assayed by a rat-paw pressure test (RPP) (MPE50 = 24, 26, 8.3, and 12 mg/kg, respectively). The R,R-trans isomer, 38, was inactive in binding and RPP. The analgesic effect was reversed by administration of naloxone, confirming these effects are opioid in character. Optimal activity is produced when the basic nitrogen atom is in a pyrrolidine ring, the aryl group is a 10-pi-electron-rich aromatic system, such as 4-benzo[b]thiophene, 4-benzo[b]furan, or 4-chlorophenoxy, and overall lipophilicity lies within the range log P = 3.5-5.0.