Receptor mechanisms underlying the in vivo effects of nicotinic acetylcholine receptor (nAChR) drugs need to be determined to better understand possible differences in therapeutic potential. This study compared the effects of agonists that are reported either to differ in intrinsic activity (i.e., efficacy) at α4β2 nAChR in vitro or to have in vivo effects consistent with differences in efficacy. The drugs included nicotine, varenicline, cytisine, epibatidine, and three novel epibatidine derivatives: 2'-fluoro-3'-(4-nitrophenyl)deschloroepibatidine (RTI-7527-102), 2'-fluorodeschloroepibatidine (RTI-7527-36), and 3'-(3″-dimethylaminophenyl)-epibatidine (RTI-7527-76). Mice discriminated nicotine base (1 mg/kg base) from saline; other mice were used to measure rectal temperature. In the nicotine discrimination assay, the maximum percentage of nicotine-appropriate responding varied: 92 % for nicotine, 84 % for epibatidine, 77 % for RTI-7527-36, and 71 % for varenicline and significantly less for RTI-7527-76 (58 %), RTI-7527-102 (46 %), and cytisine (33 %). Each drug markedly decreased rectal temperature by as much as 12 ºC. The rank-order potency in the discrimination and hypothermia assays was epibatidine > RTI-7527-36 > nicotine > RTI-7527-102 > varenicline = cytisine = RTI-7527-76. The nAChR antagonist mecamylamine (3.2 mg/kg) antagonized the discriminative stimulus effects of epibatidine and RTI-7527-102, as well as the hypothermic effects of every drug except cytisine. The β2-subunit selective nAChR antagonist dihydro-β-erythroidine (DHβE; up to 10 mg/kg) antagonized hypothermic effects but less effectively so than mecamylamine. The marked hypothermic effects of all drugs except cytisine are due in part to agonism at nAChR containing β2-subunits. Differential substitution for the nicotine discriminative stimulus is consistent with differences in α4β2 nAChR efficacy; however, collectively the current results suggest that multiple nAChR receptor subtypes mediate the effects of the agonists.