Preclinical medication development for stimulant use disorder

National Institute On Drug Abuse

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Abstract

Significant progress was made on this project, which involves the preclinical development of candidate medications for stimulant use disorders. Four relevant manuscripts were published in peer-reviewed journals over the last year. Two articles characterize the pharmacology of novel 5-HT2A receptor agonists in mice, whereas two other articles describe methodological advances for determining the mechanism of drug action in vitro and in vivo. Emerging evidence suggests that psychedelic-assisted therapies could be useful for treating substance use disorders, but the intensity of acute 5-HT2A-mediated subjective effects can be problematic for some patients. In an original research publication, our team at NIDA IRP reported that serotonin-1A (5-HT1A) receptor activation by tryptamines, such as 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), can markedly reduce their acute psychedelic-like effects in mice (Glatfelter et al., 2024). Our preclinical findings suggest that the balance between 5-HT1A and 5-HT2A agonism might be leveraged to develop psychedelic medications with less intense subjective effects. 5-MeO-DMT analogs are used as recreational drugs, but they are also being developed as potential medicines, warranting further investigation into their pharmacology. We investigated in vitro receptor profiles and acute in vivo effects of 5-MeO-DMT and several of its N-alkyl analogs to examine the influence of 5-HT1A receptors on 5-HT2A-mediated psychedelic-like effects in the mouse head twitch response (HTR) model. In vitro binding and functional assays showed that all 5-MeO-DMT analogs bind to and activate multiple receptor targets, including potent effects at 5-HT1A and 5-HT2A receptors. In C57Bl/6J mice, subcutaneous injection of the analogs induced HTRs with varying potencies (ED50 range = 0.2 – 1.8 mg/kg) and maximal effects (Emax range = 20 – 60 HTRs/ 30 min), while also inducing hypothermia and hypolocomotion at higher doses (ED50 range = 3.2 – 20.6 mg/kg). 5-HT2A antagonist pretreatment blocked drug-induced HTRs, whereas 5-HT1A antagonist pretreatment enhanced HTRs. Interestingly, blockade of 5-HT1A receptors unmasked latent HTR activity for the N-ethyl homolog and markedly increased maximal responses for all other HTR-active analogs (40 – 90 HTRs/ 30 min), supporting the notion that 5-HT1A agonist activity suppresses 5-HT2A-induced HTRs. Overall, our findings provide key information about the structure activity relationships for 5-MeO-DMT analogs to induce psychedelic-like effects, their overall target profiles, and suggest that increasing the degree of 5-HT1A receptor agonism may be a viable strategy to dampen acute psychoactive effects of 5-HT2A agonists.