Receptor binding profiles and quantitative structure-affinity relationships of some 5-substituted-N,N-diallyltryptamines.
Nicholas V. Cozzi, Paul F. Daley
Bioorganic & Medicinal Chemistry Letters February 1, 2016 DOI: 10.1016/j.bmcl.2015.12.053 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro binding study with quantitative structure-affinity relationship analysis Peer reviewed |
|---|---|
| Topics | 5-MeO-DMT |
| Keywords | 5-Methoxy-N,N-Diallyltryptamine Dalt Hallucinogen Psychopharmacology Qsar Receptor binding Psychedelic compounds: psychedelic Serotonin receptors Affinities Quantitative structure-affinity relationships Molecular structure Drug development Compound synthesis |
| Citations | 24 |
| Key points | Multiple serotonin receptors and several nonserotonergic sites likely contribute to the psychoactive effects of DALT compounds, with binding affinities correlated to steric, electronic, and hydrophobic properties. |
Abstract
N,N-Diallyltryptamine (DALT) and 5-methoxy-N,N-diallyltryptamine (5-MeO-DALT) are two tryptamines synthesized and tested by Alexander Shulgin. In self-experiments, 5-MeO-DALT was reported to be psychoactive in the 12-20mg range, while the unsubstituted compound DALT had few discernible effects in the 42-80 mg range. Recently, 5-MeO-DALT has been used in nonmedical settings for its psychoactive effects, but these effects have been poorly characterized and little is known of its pharmacological properties. We extended the work of Shulgin by synthesizing additional 5-substituted-DALTs. We then compared them to DALT and 5-MeO-DALT for their binding affinities at 45 cloned receptors and transporter proteins. Based on in vitro binding affinity, we identified 27 potential receptor targets for the 5-substituted-DALT compounds. Five of the DALT compounds had affinity in the 10-80 nM range for serotonin 5-HT1A and 5-HT2B receptors, while the affinity of DALT itself at 5-HT1A receptors was slightly lower at 100 nM. Among the 5-HT2 subtypes, the weakest affinity was at 5-HT2A receptors, spanning 250-730 nM. Five of the DALT compounds had affinity in the 50-400 nM range for serotonin 5-HT1D, 5-HT6, and 5-HT7 receptors; again, it was the unsubstituted DALT that had the weakest affinity at all three subtypes. The test drugs had even weaker affinity for 5-HT1B, 5-HT1E, and 5-HT5A subtypes and little or no affinity for the 5-HT3 subtype. These compounds also had generally nanomolar affinities for adrenergic α2A, α2B, and α2C receptors, sigma receptors σ1 and σ2, histamine H1 receptors, and norepinephrine and serotonin uptake transporters. They also bound to other targets in the nanomolar-to-low micromolar range. Based on these binding results, it is likely that multiple serotonin receptors, as well as several nonserotonergic sites are important for the psychoactive effects of DALT drugs. To learn whether any quantitative structure-affinity relationships existed, we evaluated correlations among physicochemical properties of the congeneric 5-substituted-DALT compounds. The descriptors included electronic (σp), hydrophobic (π), and steric (CMR) parameters. The binding affinity at 5-HT1A, 5-HT1D, 5-HT7, and κ opioid receptors was positively correlated with the steric volume parameter CMR. At α2A, α2B, and α2C receptors, and at the histamine H1 receptor, binding affinity was correlated with the Hammett substituent parameter σp; higher affinity was associated with larger σp values. At the σ2 receptor, higher affinity was correlated with increasing π. These correlations should aid in the development of more potent and selective drugs within this family of compounds.
Comparable studies
Other preclinical and animal studies on 5-MeO-DMT, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psychedelic N,N-dimethyltryptamine and 5-methoxy-N,N-dimethyltryptamine modulate innate and adaptive inflammatory responses through the sigma-1 receptor of human monocyte-derived dendritic cells. Human primary monocyte-derived dendritic cells | 2014 | In vitro study | |
| Effects of N,N-Dimethyltryptamine on Rat Behaviors Relevant to Anxiety and Depression Adult male Sprague-Dawley rats | 2018 | Experimental study | |
| Hallucinogen-like actions of 5-methoxy-N,N-diisopropyltryptamine in mice and rats. Mice and rats | 2006 | Preclinical study | |
| Agonist Properties of N,N-Dimethyltryptamine at Serotonin 5-HT2A and 5-HT2C Receptors Rats and transfected fibroblasts | 1998 | Experimental study | |
| Subtypes of the 5-HT receptor mediating the behavioural responses to 5-methoxy-N,N-dimethyltryptamine in the rat Intact rats and rats depleted of monoamines with reserpine | 1985 | Experimental study |
Citations in the library
Cited by 16
- Investigation of the Structure–Activity Relationships of Psilocybin Analogues ACS Pharmacology & Translational Science December 14, 2020
- Serotonergic Psychedelics: Experimental Approaches for Assessing Mechanisms of Action Handbook of experimental pharmacology 2018
- Population Survey Data Informing the Therapeutic Potential of Classic and Novel Phenethylamine, Tryptamine, and Lysergamide Psychedelics Frontiers in Psychiatry February 11, 2020
- Receptor binding profiles and behavioral pharmacology of ring-substituted N,N-diallyltryptamine analogs. Neuropharmacology November 1, 2018
- Locomotor and discriminative stimulus effects of four novel hallucinogens in rodents. Behavioural Pharmacology August 1, 2017
and 11 more in the library
Cites 10
- Structural Basis for Molecular Recognition at Serotonin Receptors Science March 22, 2013
- The effects of non-medically used psychoactive drugs on monoamine neurotransmission in rat brain. European Journal of Pharmacology March 22, 2007
- Agonist Properties of N,N-Dimethyltryptamine at Serotonin 5-HT2A and 5-HT2C Receptors Pharmacology, Biochemistry, and Behavior November 1, 1998
- The recreational tryptamine 5-MeO-DALT (N,N-diallyl-5-methoxytryptamine): a brief review. Progress in Neuro-Psychopharmacology and Biological Psychiatry December 3, 2012
- An investigation of the stability of emerging new psychoactive substances Drug Testing and Analysis November 4, 2013
and 5 more in the library