Serotonin 1A Receptors Modulate Serotonin 2A Receptor-Mediated Behavioral Effects of 5-Methoxy- N , N -dimethyltryptamine Analogs in Mice

• Published in: ACS chemical neuroscience 2024-12
• Main Authors: Glatfelter, Grant C, Clark, Allison A, Cavalco, Natalie G, Landavazo, Antonio, Partilla, John S, Naeem, Marilyn, Golen, James A, Chadeayne, Andrew R, Manke, David R, Blough, Bruce E, McCorvy, John D, Baumann, Michael H
• Format: Article
• Language: English
• ISSN: 1948-7193
• DOI: 10.1021/acschemneuro.4c00513

5-methoxy- , -dimethyltrytpamine (5-MeO-DMT) analogs are used as recreational drugs, but they are also being developed as potential medicines, warranting further investigation into their pharmacology. Here, we investigated the neuropharmacology of 5-MeO-DMT and several of its -alkyl, -allyl, and 2-methyl analogs, with three major aims: 1) to determine in vitro receptor profiles for the compounds, 2) to characterize in vitro functional activities at serotonin (5-HT) 2A receptors (5-HT ) and 1A receptors (5-HT ), and 3) to examine the influence of 5-HT on 5-HT -mediated psychedelic-like effects in the mouse head twitch response (HTR) model. In vitro receptor binding and functional assays showed that all 5-MeO-DMT analogs bind with high affinity and activate multiple targets (e.g., 5-HT receptor subtypes, alpha adrenergic receptors), including potent effects at 5-HT and 5-HT . In C57Bl/6J mice, subcutaneous injection of the analogs induced HTRs with varying potencies (ED range = 0.2-1.8 mg/kg) and maximal effects ( range = 20-60 HTRs/30 min), while inducing hypothermia and hypolocomotion at higher doses (ED range = 3.2-20.6 mg/kg). 5-HT antagonist pretreatment blocked drug-induced HTRs, whereas 5-HT antagonist pretreatment enhanced HTRs. In general, , -dialkyl and -isopropyl derivatives displayed HTR activity, while the -methyl, -ethyl, and 2-methyl analogs did not. Importantly, blockade of 5-HT unmasked latent HTR activity for the -ethyl analog and markedly increased maximal responses for other HTR-active compounds (40-90 HTRs/30 min), supporting the notion that 5-HT agonist activity can dampen 5-HT -mediated HTRs. Suppression of 5-HT -mediated HTRs by 5-HT only occurred after high 5-MeO-DMT doses, suggesting involvement of other receptors in modulating psychedelic-like effects. Overall, our findings provide key information about the receptor target profiles for 5-MeO-DMT analogs, the structure-activity relationships for inducing psychedelic-like effects, and the critical role of 5-HT agonism in modulating acute psychoactive effects of 5-HT agonists.