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Stimulus properties of PMMA: effect of optical isomers and conformational restriction
1Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond 23298-0540, USA.
Abstract:
para-Methoxymethamphetamine (PMMA), a structural hybrid of two central stimulants, lacks stimulant properties but behaves in a manner similar to that of MDMA [N-methyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane]. PMMA has been established as a training drug in drug discrimination studies, and in the present investigation we sought to determine which optical isomer of PMMA is primarily responsible for its stimulus effects. Because PMMA is a conformationally flexible molecule, it was also of interest to determine what conformation 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 at least as potent as PMMA (ED50 = 0.41 mg/kg), whereas R(-)PMMA failed to result in complete stimulus generalization. An aminotetralin-like conformation, as found in PMMA-AT (ED50 = 0.29 mg/kg), seems to better account for the actions of PMMA than a tetrahydroisoquinoline-like conformation because TIQ-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 considerable similarity with respect to their stimulus properties in animals except that PMMA lacks the amphetaminergic stimulant component of action associated with MDMA.
Insights
The S(+) isomer of para-methoxymethamphetamine (PMMA) is primarily responsible for its stimulus effects, unlike the R(-) isomer. A specific conformation, aminotetralin-like, is crucial for PMMA
Area of Science:
- Neuroscience
- Pharmacology
- Medicinal Chemistry
Background:
- Para-methoxymethamphetamine (PMMA) is a structural analog of MDMA.
- PMMA exhibits stimulus effects similar to MDMA but lacks stimulant properties.
- Understanding PMMA's isomers and conformations is key to its pharmacological action.
Purpose of the Study:
- To identify the specific optical isomer of PMMA responsible for its stimulus effects.
- To investigate the role of molecular conformation in PMMA's pharmacological activity.
- To compare the stimulus properties of PMMA with MDMA.
Main Methods:
- Synthesis and examination of S(+)PMMA, R(-)PMMA, and conformationally restricted analogs (PMMA-AT, TIQ-1, TIQ-2).
- Drug discrimination studies to assess stimulus generalization and potency (ED50).
- Analysis of structure-activity relationships for PMMA and its analogs.
Main Results:
- S(+)PMMA demonstrated significant stimulus effects (ED50 = 0.32 mg/kg), comparable to racemic PMMA (ED50 = 0.41 mg/kg).
- R(-)PMMA did not produce complete stimulus generalization, indicating lower activity.
- The aminotetralin-like conformation (PMMA-AT, ED50 = 0.29 mg/kg) was more effective than the tetrahydroisoquinoline-like conformation (TIQ-1, TIQ-2).
Conclusions:
- The S(+) isomer of PMMA is primarily responsible for its stimulus effects in drug discrimination studies.
- An aminotetralin-like conformation is critical for PMMA's observed actions.
- PMMA's stimulus properties in animals are similar to MDMA, but PMMA lacks the amphetaminergic component characteristic of MDMA.