| Autor: |
Glatfelter GC; Designer Drug Research Unit, National Institute on Drug Abuse, Intramural Research Program, Baltimore, Maryland 21224, United States., Clark AA; Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, United States., Cavalco NG; Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, United States., Landavazo A; Center for Drug Discovery, Research Triangle Institute, Research Triangle Park, North Carolina 27709, United States., Partilla JS; Designer Drug Research Unit, National Institute on Drug Abuse, Intramural Research Program, Baltimore, Maryland 21224, United States., Naeem M; Department of Chemistry and Biochemistry, University of Massachusetts Dartmouth, North Dartmouth, Massachusetts 02747, United States., Golen JA; Department of Chemistry and Biochemistry, University of Massachusetts Dartmouth, North Dartmouth, Massachusetts 02747, United States., Chadeayne AR; Department of Chemistry and Biochemistry, University of Massachusetts Dartmouth, North Dartmouth, Massachusetts 02747, United States.; CaaMTech, Inc., Issaquah, Washington 98027, United States., Manke DR; Department of Chemistry and Biochemistry, University of Massachusetts Dartmouth, North Dartmouth, Massachusetts 02747, United States., Blough BE; Center for Drug Discovery, Research Triangle Institute, Research Triangle Park, North Carolina 27709, United States., McCorvy JD; Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, United States.; Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, United States.; Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, United States., Baumann MH; Designer Drug Research Unit, National Institute on Drug Abuse, Intramural Research Program, Baltimore, Maryland 21224, United States. |
| Abstrakt: |
5-methoxy- N , N -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 N -alkyl, N -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 2A ) and 1A receptors (5-HT 1A ), and 3) to examine the influence of 5-HT 1A on 5-HT 2A -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 2A and 5-HT 1A . In C57Bl/6J mice, subcutaneous injection of the analogs induced HTRs with varying potencies (ED 50 range = 0.2-1.8 mg/kg) and maximal effects ( E max range = 20-60 HTRs/30 min), while inducing hypothermia and hypolocomotion at higher doses (ED 50 range = 3.2-20.6 mg/kg). 5-HT 2A antagonist pretreatment blocked drug-induced HTRs, whereas 5-HT 1A antagonist pretreatment enhanced HTRs. In general, N , N -dialkyl and N -isopropyl derivatives displayed HTR activity, while the N -methyl, N -ethyl, and 2-methyl analogs did not. Importantly, blockade of 5-HT 1A unmasked latent HTR activity for the N -ethyl analog and markedly increased maximal responses for other HTR-active compounds (40-90 HTRs/30 min), supporting the notion that 5-HT 1A agonist activity can dampen 5-HT 2A -mediated HTRs. Suppression of 5-HT 2A -mediated HTRs by 5-HT 1A 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 1A agonism in modulating acute psychoactive effects of 5-HT 2A agonists. |
