Contribution of a helix 5 locus to selectivity of hallucinogenic and nonhallucinogenic ligands for the human 5-hydroxytryptamine2A and 5-hydroxytryptamine2C receptors: direct and indirect effects on ligand affinity mediated by the same locus.
N Almaula, Barbara J. Ebersole, J A Ballesteros, Harel Weinstein, Stuart C. Sealfon
Molecular Pharmacology July 1, 1996 DOI: 10.1016/s0026-895x(25)09149-7 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Theoretical or philosophical paper Peer reviewed |
|---|---|
| Topics | LSD |
| Keywords | Cell line Animals Humans Rats Ergolines Ketanserin Phosphatidylinositols Receptors, serotonin Receptor, serotonin, 5-ht2a Receptor, serotonin, 5-ht2c Recombinant proteins Hallucinogens Ligands Transfection Mutagenesis, site-directed Binding sites Binding, competitive Amino acid sequence Protein structure, secondary Structure-activity relationship Kinetics Point mutation Models, molecular Molecular sequence data Chlorocebus aethiops |
| Key points | The amino acid at position 5.46 directly determines relative ligand selectivity only for ergolines, and may contribute to the specific effects of hallucinogens in that class. For DOI and ketanserin, this locus contributes little to selectivity. Indoleamines appear to interact directly with this side chain in the 5-HT2A receptor but not the 5-HT2C receptor, and the higher affinity of serotonin and tryptamine for 5-HT2C is not due to this locus. |
Abstract
An important determinant of the neurobehavioral responses induced by a drug is its relative receptor selectivity. The molecular basis of ligand selectivity of hallucinogenic and nonhallucinogenic compounds of varying structural classes for the human 5-hydroxytryptamine (5-HT)2A and 5-HT2C receptors was investigated with the use of reciprocal site-directed mutagenesis. Because these two closely related receptor subtypes differ in the amino acid present at position 5.46 (residues 242 and 222 in the sequences, respectively), the effects of corresponding substitutions in the 5-HT2A[S5.46(242)-->A] and 5-HT2C[A5.46(222)-->S] receptors were studied in tandem. By studying both receptors, the direct and indirect effects of mutations on affinity and selectivity can be distinguished. The ergolines studied, mesulergine (selective for the 5-HT2C receptor) and d-lysergic acid diethylamide (selective for the 5-HT2A receptor), reversed their relative affinity with mutations in each receptor, supporting a direct role of this locus in the selectivity of these ligands. However, interchange mutations in either receptor led to decreased or unchanged affinity for (+/-)-1-)(2,5-dimethoxy-4-iodophenyl)-2-aminopropane and ketanserin, which have higher affinity for the 5-HT2A receptor, consistent with little contribution of this locus to the selectivity of these ligands. The indoleamines studied were affected differently by mutations in each receptor, suggesting that they bind differently to the two receptor subtypes. Mutation of this locus in the 5-HT2A receptor decreased the affinity of all indoleamines, whereas the interchange mutation of the 5-HT2C receptor did not affect indoleamine affinity. These results are consistent with a direct interaction between this side chain and indoleamines for the 5-HT2A receptor but not for the 5-HT2C receptor. Furthermore, this analysis shows that the higher affinity of 5-HT and tryptamine for the 5-HT2C receptor than for the 5-HT2A receptors is not due to the difference at this locus. The hallucinogens studied [d-lysergic acid diethylamide, psilocin, bufotenin, and (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane] fell into different classes in this analysis. For the classes of ligand studied, the side-chain difference at this position directly determines relative ligand selectivity only for ergolines and may contribute to the specific effects of hallucinogens in this class.
Comparable studies
Other theoretical and historical papers on LSD, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| The Experimental Use of Psychedelic (LSD) Psychotherapy | 1970 | Historical analysis | |
| LSD: My Problem Child | 1981 | Historical analysis | |
| On the Use and Abuse of LSD | 1968 | Theoretical or philosophical paper | |
| The Use of Music in Psychedelic (LSD) Psychotherapy | 1972 | Theoretical or philosophical paper | |
| Flashbacks: Recurrent Intrusive Images After the Use of LSD | 1969 | Theoretical or philosophical paper |
Citations in the library
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- Transcriptional regulation in the rat prefrontal cortex and hippocampus after a single administration of psilocybin Journal of Psychopharmacology November 4, 2020
- 1-Aminomethylbenzocycloalkanes: conformationally restricted hallucinogenic phenethylamine analogues as functionally selective 5-HT2A receptor agonists. Journal of Medicinal Chemistry September 21, 2006
- Ligand-Dependent Conformations and Dynamics of the Serotonin 5-HT2A Receptor Determine Its Activation and Membrane-Driven Oligomerization Properties PLoS Computational Biology April 19, 2012
- Molecular basis of partial agonism: orientation of indoleamine ligands in the binding pocket of the human serotonin 5-HT2A receptor determines relative efficacy. Molecular Pharmacology 2003
- Bufotenine: toward an understanding of possible psychoactive mechanisms. Journal of Psychoactive Drugs 2000
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