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].
AL-38022A is a novel synthetic serotonergic (5-HT) ligand that exhibited high affinity for each of the 5-HT2 receptor subtypes (Ki<or=2.2 nM), but a significantly lower (>100-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.
May
Jesse A
JA
Ophthalmology Discovery Research, Alcon Research, Ltd., 6201 South Freeway, Fort Worth, Texas 76134, United States. jesse.may@alconlabs.com
Sharif
Najam A
NA
Chen
Hwang-Hsing
HH
Liao
John C
JC
Kelly
Curtis R
CR
Glennon
Richard A
RA
Young
Richard
R
Li
Jun-Xu
JX
Rice
Kenner C
KC
France
Charles P
CP
D004290:DOM 2,5-Dimethoxy-4-Methylamphetamine / Q000494:pharmacology; D058666:Adrenergic beta-2 Receptor Agonists; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D020013:Calcium Signaling / Q000187:drug effects; D002627:Chemistry, Physical; D003001:Cloning, Molecular; D000242:Cyclic AMP / Q000096:biosynthesis / Q000235:genetics; D004192:Discrimination, Psychological / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004355:Drug Stability; D005464:Fluorobenzenes / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007191:Indazoles / Q000494:pharmacology*; D008253:Macaca mulatta; D008297:Male; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A / Q000187:drug effects; D044405:Receptor, Serotonin, 5-HT2C / Q000187:drug effects; D058826:Serotonin 5-HT2 Receptor Agonists; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000737:chemistry / Q000494:pharmacology*; D013270:Stomach / Q000187:drug effects
C539491:2-(8,9-dihydro-7H-pyrano(2,3-g)indazol-1-yl)-1-methylethylamine; D058666:Adrenergic beta-2 Receptor Agonists; D001578:Benzopyrans; D005464:Fluorobenzenes; D007191:Indazoles; D010880:Piperidines; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D058826:Serotonin 5-HT2 Receptor Agonists; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D004290:DOM 2,5-Dimethoxy-4-Methylamphetamine; D000242:Cyclic AMP; C079049:volinanserin