Antagonism of 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane stimulus with a newly identified 5-HT2- versus 5-HT1C-selective antagonist

Abstract

DOM [i.e., 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane] is a 5-HT1C/2 serotonin agonist that exerts stimulus control of behavior in animals. In order to determine if the discriminative stimulus effect of DOM is 5-HT1C- or 5-HT2-mediated, it would be informative to conduct tests of stimulus antagonism with a 5-HT1C- or 5-HT2-selective antagonist. To date, no such agents exist. Although the neuroleptic agent spiperone binds at D2 dopamine receptors and 5-HT1A serotonin receptors, (a) it displays about a 1000-fold selectivity for 5-HT2 versus 5-HT1C sites and (b) it has been used as a "5-HT2-selective" antagonist. Because spiperone is a behaviorally disruptive agent, it is not suitable for use in drug-discrimination studies. Using the spiperone molecule as a starting point, a limited structure-affinity investigation was conducted in order to identify a suitable antagonist with high affinity and selectivity for 5-HT2 receptors, and yet an antagonist that might lack the disruptive actions of spiperone. Various modifications of the spiperone molecule were examined, but most resulted in decreased 5-HT2 affinity or in loss of selectivity. One compound, 8-[3-(4-fluorophenoxy)propyl]-1-phenyl-1,3,8-triazaspiro[4.5]de can-4-on e (26), was shown to bind at 5-HT2 sites with high affinity (Ki = 2 nM) and > 2,000-fold selectivity versus 5-HT1C sites. In tests of stimulus antagonism using rats trained to discriminate 1 mg/kg of DOM from saline vehicle, 26 behaved as a potent antagonist (ED50 = 0.003 mg/kg) and lacked the disruptive effects associated with spiperone. As such, (a) it would appear that the DOM stimulus is primarily a 5-HT2-mediated, and not 5-HT1C-mediated, phenomenon, and (b) compound 26 may find application in other pharmacologic investigations where spiperone may not be a suitable antagonist.

Sila‐Haloperidol, a Silicon Analogue of the Dopamine (D2) Receptor Antagonist Haloperidol: Synthesis, Pharmacological Properties, and Metabolic Fate

“…Reaction of 6 with methanesulfonyl chloride in the presence of triethylamine, followed by the addition of sodium iodide, afforded the bis(2-iodoethyl)silane 7 (81 % yield). Treatment of 7 with 3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propylamine [12] (8) gave the cyclization product, the 4-silapiperidine 9 (50 % yield). Deprotection of 9 by treatment with hydrochloric acid afforded the title compound as the hydrochloride (sila-haloperidol hydrochloride, 1 b·HCl, 71 % yield).…”

Serotonergic modulation of the discriminative-stimulus effects of cocaine in squirrel monkeys

“…More recent studies with highly selective 5-HT receptor agonists and antagonists have confirmed earlier findings and implicated 5-HT 2 receptors as the primary mechanism involved in quipazine discrimination. A variety of 5-HT 2 -selective agonists can exert stimulus control over behavior (Glennon 1991;Ismaiel et al 1993), and 5-HT 2 -selective agonists substitute for quipazine, whereas 5-HT 2 -selective antagonists readily block quipazine discrimination (Glennon et al 1983;Friedman et al 1984;Smith et al 1995). Moreover, studies have demonstrated 5-HT 2 receptor involvement in quipazine-induced suppression of schedule-controlled operant behavior in squirrel monkeys (McKearney 1990), and in quipazine-induced anorexia in rodents (Hewson et al 1988;Skukla et al 1990).…”

Enzymatic Baeyer–Villiger Oxidation of Benzaldehydes

“…Fluorophenols can serve as synthons for the production of drugs, including enzyme inhibitors [2,3] and receptor antagonists. [4] Catecholamines and amino acids with a radiolabelled [ 18 F]-fluorophenol moiety have found applications for the in vivo imaging of amino acid metabolism [5] and protein synthesis [6] using positron emission tomography (PET). [7] Chemical methods to produce fluorophenols include diazotization/Sandmeyer decomposition with fluoroanilines, diazotization/thermal decomposition with aminophenols, alkaline hydrolysis with substituted fluorobenzene and F 2 /N 2 gas/liquid phase conversion with phenol.…”