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

Dec 5, 2024ACS chemical neuroscience

Serotonin 1A Receptors Influence Behavioral Responses to Serotonin 2A Receptor Activation by 5-MeO-DMT-Like Compounds in Mice

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Abstract

All 5-MeO-DMT analogs bind with high affinity and activate multiple receptors, including 5-HT receptor subtypes.

5-MeO-DMT analogs demonstrated varying potencies in inducing head twitch responses in mice, with effective doses ranging from 0.2 to 1.8 mg/kg.
The maximum induced head twitch responses varied from 20 to 60 responses per 30 minutes, depending on the analog used.
Higher doses of the analogs (3.2-20.6 mg/kg) led to hypothermia and decreased movement in mice.
Blocking serotonin receptors with antagonists prevented head twitch responses, while pre-treatment with serotonin antagonists increased these responses.
Certain analogs, such as the dialkyl and isopropyl derivatives, showed significant head twitch activity, while others did not.
The effects of serotonin appeared to dampen the head twitch responses induced by 5-MeO-DMT analogs, particularly at higher doses.

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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-HTon 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-HTand 5-HT. In C57Bl/6J mice, subcutaneous injection of the analogs induced HTRs with varying potencies (EDrange = 0.2-1.8 mg/kg) and maximal effects (range = 20-60 HTRs/30 min), while inducing hypothermia and hypolocomotion at higher doses (EDrange = 3.2-20.6 mg/kg). 5-HTantagonist pretreatment blocked drug-induced HTRs, whereas 5-HTantagonist 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-HTunmasked 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-HTagonist activity can dampen 5-HT-mediated HTRs. Suppression of 5-HT-mediated HTRs by 5-HTonly 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-HTagonism in modulating acute psychoactive effects of 5-HTagonists. N N N N E N N N N N N2A1A1A2A2A1A50max50 2A1A1A1A2A2A1A1A2A

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

Abstract

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