Bioproduction platform using a novel cane toad (Rhinella marina) N-methyltransferase for psychedelic-inspired drug discovery
Xue Chen, Jing Li, Lisa Yu, D. Dhananjaya, Francesca Maule, Sarah G. Cook, Li‐mei Chang, Jonathan Gallant, David Press, Jaideep S. Bains, Sheetal A. Raithatha, Jillian M. Hagel, Peter J. Facchini
Research Square March 10, 2023 DOI: 10.21203/rs.3.rs-2667175/v1 via OpenAlex
Summary
AI-generated from the abstractAn enzyme from cane toad (Rhinella marina), named RmNMT, efficiently produces N,N-dimethylated indolethylamines, including psychedelic compounds like N,N-dimethyltryptamine. Unlike similar enzymes in mammals and fungi, RmNMT is highly efficient and promiscuous, enabling the bioproduction of new-to-nature indolethylamine derivatives. N,N-Dimethylated indolethylamines showed reduced binding and activation at 5-HT1A and 5-HT2A receptors compared to primary amines, yet only these tertiary amines induced hallucinogenic behavior in mice, suggesting metabolic stability is key. This discovery establishes a platform for producing and screening novel indolethylamines for potential psychiatric medicines.
Study at a glance
| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Mice |
| Interventions | N N-dimethylated indolethylamines |
| Keywords | Bioproduction Drug discovery Toad Cane Biology |
| Key finding | The cane toad enzyme RmNMT enables efficient bioproduction of N,N-dimethylated indolethylamines, which despite reduced 5-HT2A receptor engagement, are the only ones that induce hallucinogenic behavior in mice. |
Abstract
Abstract Psychedelic indolethylamines have emerged as potential medicines to treat several psychiatric pathologies. Natural sources of these compounds include ‘magic mushrooms’, plants used to prepare ahayuasca, and toads. Owing to the occurrence of indolethylamines such as N,N-dimethyltryptamine, toad skin and parotid gland preparations have a history of ceremonial use, yet their biosynthesis remains uncharacterized. We report the isolation of an indolethylamine N-methyltransferase (RmNMT) from cane toad (Rhinella marina). Unlike functionally similar mammalian and fungal enzymes, the efficiency and promiscuity of RmNMT made it suitable for the bioproduction of new-to-nature indolethylamine derivatives. N,N-Dimethylated indolethylamines showed reduced affinity and engagement at 5-HT1A and 5-HT2A receptors respectively, compared with primary amine equivalents. Despite reduced 5-HT2A receptor engagement of tertiary amines, only these molecules induced hallucinogenic behavior in mice underscoring the importance of metabolic stability. The discovery of RmNMT facilitated the establishment of a bioproduction platform for the isolation and pharmacological screening of novel indolethylamines.