AbstractTwo novel series, Ia,b and IIa,b, ofkappaopioid antinociceptive agents have recently been described.2a,b,3a,b,cThe biological activities of 16 racemic compounds and their corresponding (−) enantiomers are now compared in a battery of tests. Enantiomers of unsubstituted piperidinesIawere synthesized starting from S(−) pipecolic acid, whereas the enantiomerically pure substituted piperidines (Ib), tetrahydroisoquinolines (IIa), and thienopiperidines (IIb) were, in general, obtained after diastereomeric crystallization of the corresponding tartrate salts. The absolute stereochemistry of one representative enantiomer from seriesIIawas determined to be (1S) by X‐ray crystallographic analysis. Antinociceptive activity in the mouse abdominal constriction and tail‐flick tests following subcutaneous administration, and binding affinity for κ and μ receptors, were found to reside predominantly in the (−) enantiomers. Consequently, racemic compounds showed approximately half potency of the corresponding enantiomers. This potency difference was less clear after oral administration presumably due to small differences in bioavailability of the two corresponding enantiomers.For compounds with some affinity also for μ receptors (Ki<1,000 nM), the κ/μ selectivity was maintained within each enantiomeric pair, in contrast to results found for ot