Stimulus properties of PMMA: Effect of optical isomers and conformational restriction

para-Methoxymethamphetamine (PMMA), a structural hybrid of two central stim ulants, lacks stimulant properties but behaves in a manner similar to that of MDMA [N-methyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane]. PMMA has be en established as a training drug in drug discrimination studies, and in th e present investigation we sought to determine which optical isomer of PMMA is primarily responsible for its stimulus effects. Because PMMA is a confo rmationally flexible molecule, it was also of interest to determine what co nformation is most important for its actions., Accordingly, we prepared and examined S(+)PMMA, R(-)PMMA, and conformationally restricted forms of PMMA : PMMA-AT, TIQ-1, and TIQ-2. S(+)PMMA (ED50 = 0.32 mg/kg) was found to be a t least as potent as PMMA (ED50 = 0.41 mg/kg), whereas R(-)PMMA failed to r esult in complete stimulus generalization. An aminotetralin-like conformati on, as found in PMMA-AT (ED50 = 0.29 mg/kg), seems to better account for th e actions of PMMA than a tetrahydroisoquinoline-like conformation because T IQ-1 and TIQ-2 failed to result in stimulus generalization. The results of the present study further support the concept that PMMA and MDMA share cons iderable similarity with respect to their stimulus properties in animals ex cept that PMMA lacks the amphetaminergic stimulant component of action asso ciated with MDMA. (C) 1999 Elsevier Science Inc.