CaaMTech 5-MeO-DMT Analog Research Unveils Serotonin 2A Receptor Modulation

A new research paper by scientists from CaaMTech, NIDA, RTI, UMass Dartmouth and The Medical College of Wisconsin furthers tryptamine SAR understanding

CaaMTech’s most recent contribution to peer-reviewed literature highlights the company’s continued neuroscientific research and reveals previously undiscovered interactions between serotonin receptor subtypes.  “Serotonin 1A Receptors Modulate Serotonin 2A Receptor-Mediated Behavioral Effects of 5-Methoxy-N,N-dimethyltryptamine Analogs in Mice” was published in the journal ACS Chemical Neuroscience and brought together researchers from industry, government, and academia, including CaaMTech, the Designer Drug Research Unit (DDRU) at the National Institute on Drug Abuse (NIDA) Intramural Research Program (IRP), the Research Triangle Institute (RTI) Center for Drug Discovery, the Manke Lab at UMass Dartmouth, and the McCorvy Lab at The Medical College of Wisconsin.

Many psychedelic compounds closely resemble the neurotransmitter serotonin (5-HT) in their chemical structures, allowing them to fit into the binding pockets of serotonin receptors.  But small differences in the chemical structures of psychedelics alter their affinities for different subtypes of serotonin receptors and their activation of different pathways.  Therefore, these structural differences result in differing pharmacological effects.  CaaMTech and its collaborators have extensively studied the effects these structural changes have on the pharmacology of various classes of tryptamine-based compounds to determine their SARs (structure-activity relationships).

The serotonin system is responsible for regulating a broad and varying range of neurological and physiological functions, including mood.  Agonism (activation through binding of a compound to the receptor) of the 5-HT2A receptor, one subtype (2A) of serotonin receptor, has been correlated with perceptual visual and auditory distortions. Consciousness is a complex symphony of simultaneous biological processes, and psychedelic experiences are believed to be similarly complex.

5-MeO-DMT (5-methoxy-N,N-dimethyltryptamine) is a naturally occurring tryptamine found in the venom of the Sonoran Desert toad (Bufo alvarius). Also referred to as the “God molecule”, 5-MeO-DMT is a powerful psychedelic compound when inhaled, and numerous companies are attempting to develop 5-MeO-DMT based therapeutics, including GH Research and atai Life Sciences.  CaaMTech has previously synthesized and studied various 5-MeO-DMT derivatives, including orally active 5-MeO-DPT.  

5-MeO-DMT derivatives have relatively high affinities for the 5-HT1A receptor versus the 5-HT2A receptor.  As a part of their research, CaaMTech and its collaborators characterized the receptor binding profiles of 5-MeO-DMT and thirteen structurally related 5-methoxy tryptamines and investigated their in vitro functional activities at 5-HT1A and 5-HT2A receptors.  Finally, the researchers sought “to examine the influence of 5-HT1A on 5-HT2A-mediated psychedelic-like effects in the mouse head twitch response (HTR) model,” a model commonly used to predict psychedelic effects.

The researchers found that “5-HT1A antagonist pretreatment enhanced HTRs.” In other words, pre-treatment with a drug that blocks the 5-HT1A receptor causes more of the HTR effect most trusted to correlate with a human psychedelic experience resulting from agonizing the 5-HT2A receptor.  Results of the studies also showed evidence “that 5-HT1A agonist activity can dampen 5-HT2A-mediated HTRs,” demonstrating that the opposite is also true: activating the 5-HT1A receptor instead of blocking it suppresses the effects induced by agonizing the 5-HT2A receptor.  The work found further evidence that other receptor subtypes are likely involved in the mediation of the psychedelic effects induced by agonism of 5-HT2A receptors.

“CaaMTech has been honored to collaborate with talented scientists from so many different fields and institutions who have come together to better understand the symphony of interconnected effects of serotonergic drugs,” explained Dr. Andrew Chadeayne, CaaMTech CEO. “This work further demonstrates the complexity of the serotonin system.  We are only scratching the surface of fundamentally understanding the complex nature of psychedelic compounds and their effects on the brain, but we have also learned an incredible amount that will help us design better treatments for some of the world’s most challenging neurological conditions.”