Psychedelics and the Human Receptorome

Abstract

We currently understand the mental effects of psychedelics to be caused by agonism or partial agonism of 5-HT2A (and possibly 5-HT2C) receptors, and we understand that psychedelic drugs, especially phenylalkylamines, are fairly selective for these two receptors. This manuscript is a reference work on the receptor affinity pharmacology of psychedelic drugs. New data is presented on the affinity of twenty-five psychedelic drugs at fifty-one receptors, transporters, and ion channels, assayed by the National Institute of Mental Health – Psychoactive Drug Screening Program (NIMH-PDSP). In addition, comparable data gathered from the literature on ten additional drugs is also presented (mostly assayed by the NIMH-PDSP). A new method is introduced for normalizing affinity (Ki) data that factors out potency so that the multi-receptor affinity profiles of different drugs can be directly compared and contrasted. The method is then used to compare the thirty-five drugs in graphical and tabular form. It is shown that psychedelic drugs, especially phenylalkylamines, are not as selective as generally believed, interacting with forty-two of forty-nine broadly assayed sites. The thirty-five drugs of the study have very diverse patterns of interaction with different classes of receptors, emphasizing eighteen different receptors. This diversity of receptor interaction may underlie the qualitative diversity of these drugs. It should be possible to use this diverse set of drugs as probes into the roles played by the various receptor systems in the human mind.

Psychedelics

“…Agonist or partial agonist activity at the serotonin 5-HT 2A receptor was ultimately concluded to be a necessary pharmacology for psychedelic effects, but it may not be sufficient to explain all of the qualitative differences between different drugs. As Ray (2010) pointed out, different molecules may also have significant affinity for other types of brain receptors.…”

Molecular Pharmacology and Ligand Docking Studies Reveal a Single Amino Acid Difference between Mouse and Human Serotonin 5-HT2A Receptors That Impacts Behavioral Translation of Novel 4-Phenyl-2-dimethylaminotetralin Ligands

“…Thus, other mechanisms that modulate the effects of DOI may have come into play. For example, a-adrenergic receptors may modulate activity of the 5-HT2 circuitry or be direct targets of DOI (Darmani, 1993;Ray, 2010). Relevant here is that an early (1993) NovaScreen of racemic 6-OH-7-Cl-PAT reported appreciable (K i ∼70 nM) at rat brain a 1 -adrenergic receptors yet negligible affinity for all other aminergic neurotransmitter receptors and two dozen other central nervous system receptor sites, with the known exceptions of histamine H 1 (Bucholtz et al, 1999) and 5-HT2 receptors.…”

Receptor interaction profiles of novel psychoactive tryptamines compared with classic hallucinogens

“…Tryptamines share their core structure with the neurotransmitter serotonin (5-hydroxytryptamine ). The psychoactive effects of hallucinogens, including those of tryptamines, are thought to be mediated mainly by the 5-HT 2A receptor (Glennon et al, 1984;Nichols, 2004;Titeler et al, 1988;Vollenweider et al, 1998) but may also be modulated by interactions with other targets, including other 5-HT receptors, monoamine transporters, and trace amineassociated receptors (Baumeister et al, 2014;Bunzow et al, 2001;Cozzi et al, 2009;Fantegrossi et al, 2006;McKenna et al, 1990;Nagai et al, 2007;Nichols, 2004;Ray, 2010). Structural alterations of tryptamines have been shown to result in different pharmacological and psychoactive profiles (Araujo et al, 2015;McKenna et al, 1990;Repke et al, 1985;Shulgin and Shulgin, 1997;Tittarelli et al, 2015;Trachsel et al, 2013).…”