Pharmacological properties and discriminative stimulus effects of a novel and selective 5-HT2 receptor agonist AL-38022A [(S)-2-(8,9-dihydro-7H-pyrano[2,3-g]indazol-1-yl)-1-methylethylamine].
Jesse A May, Najam A Sharif, Hwang-Hsing Chen, John C Liao, Curtis R Kelly, Richard A Glennon, Richard Young, Jun-Xu Li, Kenner C Rice, Charles P France
Pharmacology, Biochemistry, and Behavior July 30, 2008 DOI: 10.1016/j.pbb.2008.07.015 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical pharmacology study Peer reviewed |
|---|---|
| Population | Rats and monkeys (Macaca mulatta) in drug discrimination experiments; native and cloned rat and human 5-HT2 receptors in vitro |
| Interventions | AL-38022A DOM MDL 100907 |
| Topics | Serotonin |
| Keywords | Stomach Animals Macaca mulatta Humans Rats, sprague-dawley Fluorobenzenes Piperidines Indazoles Benzopyrans Receptor, serotonin, 5-ht2a Receptor, serotonin, 5-ht2c Cyclic amp Serotonin antagonists Cloning, molecular Drug stability Calcium signaling Dose-response relationship, drug Chemistry, physical Male Serotonin receptor agonists In vitro techniques Discrimination, psychological Dom 2,5-dimethoxy-4-methylamphetamine |
| Key points | AL-38022A binds with high affinity to all 5-HT2 receptor subtypes and acts as a full agonist at rat and human receptors, with low affinity for unrelated targets. It fully substitutes for the hallucinogen DOM in rat and monkey drug discrimination, and this effect is blocked by the 5-HT2A antagonist MDL 100907 in monkeys. The authors suggest it may be a useful tool for studying 5-HT2 receptor signaling. |
Abstract
AL-38022A is a novel synthetic serotonergic (5-HT) ligand that exhibited high affinity for each of the 5-HT2 receptor subtypes (Ki100-fold less) affinity for other 5-HT receptors. In addition, AL-38022A displayed a very low affinity for a broad array of other receptors, neurotransmitter transport sites, ion channels, and second messenger elements, making it a relatively selective agent. AL-38022A potently stimulated functional responses via native and cloned rat (EC50 range: 1.9-22.5 nM) and human (EC50 range: 0.5-2.2 nM) 5-HT2 receptor subtypes including [Ca2+]i mobilization and tissue contractions with apparently similar potencies and intrinsic activities and was a full agonist at all 5-HT2 receptor subtypes. The CNS activity of AL-38022A was assessed by evaluating its discriminative stimulus effects in both a rat and a monkey drug discrimination paradigm using DOM as the training drug. AL-38022A fully generalized to the DOM stimulus in each of these studies; in monkeys MDL 100907 antagonized both DOM and AL-38022A. The pharmacological profile of AL-38022A suggests that it could be a useful tool in defining 5-HT2 receptor signaling and receptor characterization where 5-HT may function as a neurotransmitter.
Comparable studies
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| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
Cited by 9
- Structure–activity relationships of serotonin 5‐HT2Aagonists Wiley Interdisciplinary Reviews Membrane Transport and Signalling February 28, 2012
- Serotonin 2A Receptor (5-HT2AR) Agonists: Psychedelics and Non-Hallucinogenic Analogues as Emerging Antidepressants Chemical Reviews November 30, 2023
- Serotonergic Psychedelics: Experimental Approaches for Assessing Mechanisms of Action Handbook of experimental pharmacology 2018
- Short- and Long-Acting Psychedelics: Structure-Activity Relationships, Pharmacology, and Implications for Neuropsychiatric Therapeutics. ACS Chemical Neuroscience June 17, 2026
- In vitro assays for the functional characterization of (psychedelic) substances at the serotonin receptor 5‐HT2AR Journal of Neurochemistry January 3, 2022
and 4 more in the library
Cites 9
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- Safety, Tolerability, and Efficacy of Psilocybin in 9 Patients With Obsessive-Compulsive Disorder The Journal of Clinical Psychiatry November 15, 2006
- Receptor binding profile suggests multiple mechanisms of action are responsible for ibogaine's putative anti-addictive activity. Psychopharmacology April 1, 1995
- 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
- Serotonin 5‐HT2A receptor activation induces 2‐arachidonoylglycerol release through a phospholipase c‐dependent mechanism Journal of Neurochemistry August 15, 2006
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