Haloperidol, haloperidol propionate, and a haloperidol analogue N-3-(p-fluorobenzoyl) propyl-4-phenyl-4-propionyl-oxypiperidine (NIH 10495) were evaluated in several in vitro and in vivo tests of opioid effects. Haloperidol bound to opioid receptors with very low affinity and had no opioid agonist effects in the other test systems. Haloperidol propionate was 10 times less potent than NIH 10495 in the binding assay and in the smooth-muscle assay. Both of these haloperidol analogues decreased the rate and volume of respiration in air and in 5% CO2 with NIH 10495 being approximately 50 times more potent than haloperidol propionate. The NIH 10495, but not the haloperidol propionate, attenuated naltrexone-like discriminative stimulus effects in morphine-dependent withdrawn rhesus monkeys. Intravenously delivered NIH 10495 maintained higher rates of responding than did haloperidol propionate when evaluated for reinforcing effects. These drugs appear to have novel spectra of action that suggest possible value for this synthetic approach to the development of clinically useful analgesics and to the development of novel neuroleptics.