A- and D-Ring Structural Modifications of an Androsterone Derivative Inhibiting 17β-Hydroxysteroid Dehydrogenase Type 3: Chemical Synthesis and Structure–Activity Relationships

Background: In recent years, there has been increasing scientific interest in the effects and pharmacology of serotonergic hallucinogens. While a large amount of experimental work has been conducted to characterize the behavioral response to hallucinogens in rodents, there has been little systematic investigation of mescaline and its analogs. The hallucinogenic potency of mescaline is increased by α-methylation and by homologation of the 4-methoxy group but it not clear whether these structural modifications have similar effects on the activity of mescaline in rodent models. Methods: In the present study, the head twitch response (HTR), a 5-HT2A receptor-mediated behavior induced by serotonergic hallucinogens, was used to assess the effects of mescaline and several analogs in C57BL/6J mice. HTR experiments were conducted with mescaline, escaline (4-ethoxy-3,5-dimethoxyphenylethylamine) and proscaline (3,5-dimethoxy-4-propoxyphenylethylamine), their α-methyl homologs TMA (3,4,5-trimethoxyamphetamine), 3C-E (4-ethoxy-3,5-dimethoxyamphetamine) and 3C-P (3,5-dimethoxy-4-propoxyamphetamine), and the 2,4,5-substituted regioisomers TMA-2 (2,4,5-trimethoxyamphetamine), MEM (4-ethoxy-2,5-dimethoxyamphetamine) and MPM (2,5-dimethoxy-4-propoxyamphetamine). Results: TMA induced the HTR and was twice as potent as mescaline. For both mescaline and TMA, replacing the 4-methoxy substituent with an ethoxy or propoxy group increased potency in the HTR assay. By contrast, although TMA-2 also induced the HTR with twice the potency of mescaline, potency was not altered by homologation of the 4-alkoxy group in TMA-2. Conclusions: The potency relationships for these compounds in mice closely parallel the human hallucinogenic data. These findings are consistent with evidence that 2,4,5- and 3,4,5-substituted phenylalkylamine hallucinogens exhibit distinct structure-activity relationships. These results provide additional evidence that the HTR assay can be used to investigate the structure-activity relationships of serotonergic hallucinogens.

Download Full-text

Insight into the Mechanism of 17β-Hydroxysteroid Dehydrogenase Type 3 Inhibition by the Androsterone Derivative RM-532-105

Current Enzyme Inhibition ◽

10.2174/1573408016999200729110245 ◽

2020 ◽

Vol 16 (3) ◽

pp. 243-250

Author(s):

Preyesh Stephen ◽

Jenny Roy ◽

René Maltais ◽

Donald Poirier

Keyword(s):

Homology Model ◽

Hydroxysteroid Dehydrogenase ◽

Enzymatic Assays ◽

Enzyme Binding ◽

Structure Activity ◽

Potential Binding ◽

Competitive Action ◽

Type 3 ◽

Insight Into ◽

Selection Of

Background: The last step in the production of androgen testosterone from 4-androstene- 3,17-dione (4-dione) in testis involves the 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3). Blocking this microsomal enzyme with an inhibitor would lower the level of testosterone and, consequently, could be an approach for the treatment of androgen-dependent diseases. RM-532-105 was developed as a steroidal inhibitor of 17β-HSD3, but its mechanism of action is not yet known. Objective: To identify potential binding sites of the 17β-HSD3 substrate 4-dione, cofactor NADPH, as well as inhibitor RM-532-105. Methods: Since there is no crystal structure of 17β-HSD3 available, complexed or not with a ligand, a homology model was prepared followed by molecular docking, and enzymatic assay experiments were performed. Results: Transfected LNCaP prostate cancer cells were used as a source of 17β-HSD3 activity for the transformation of 4-dione into testosterone in the presence of varying concentrations of a substrate, a cofactor or an inhibitor. Molecular modeling experiments and enzymatic assays with these cells suggest a competitive action of RM-532-105 with the cofactor and a non-competitive action with the substrate 4-dione. Conclusion: These results allow the selection of one inhibitor orientation in the enzyme binding site, from the two possibilities predicted by the docking experiments, and appear to be in agreement with previous structure-activity relationships.

Download Full-text