The effects of the antimalarial agent, (±)-erythro-mefloquine and related compounds [(±)-threo-mefloquine, (±)-erythro-N-methylmefloquine and its N-oxide, quinine, WR 184806 and halofanthrine] on the isolated mouse phrenic nerve diaphragm preparation were investigated. Based on their pharmacological effects, these compounds may be divided into two groups. The group I compounds, comprising (±)-erythro-mefloquine, (±)-threo-mefloquine and WR 184806, were found to exert a contractile effect on the muscle and also to inhibit the indirectly (nerve) stimulated and directly (muscle) stimulated (after α-bungarotoxin) twitch responses. The group II compounds, comprising the other compounds except halofanthrine, lacked a contractile effect on muscle but potentiated the directly stimulated twitch responses (after α-bungarotoxin). Halofanthrine did not elicit any response from the preparation.The minimum energy conformations of these compounds were determined using an interactive molecular modeling program which incorporates MMX force field for molecular mechanics calculations. Conformational analyses of the erythro and threo isomers of mefloquine hydrochloride were also undertaken using ¹H-NMR. The ¹H-NMR data supported the proposal made on the basis of MMX calculations that the erythro isomer exists in solution as one predominant conformer whereas the threo isomer is present in solution as a mixed population of two stable conformers. The structure-activity relationship of the compounds is discussed.