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

A M Ismaiel, J De Los Angeles, Milt Teitler, S Ingher, Richard A Glennon

Journal of Medicinal Chemistry August 20, 1993 DOI: 10.1021/jm00069a010 (opens in new tab)

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AI-extracted from the abstract
Characteristics Preclinical pharmacology study (drug discrimination in rats) Peer reviewed
Population Rats trained to discriminate 1 mg/kg DOM from saline
Interventions 3 DOM spiperone
Dose 1 mg/kg DOM; ED50 = 0.003 mg/kg for compound 26
Topics Serotonin
Key points Compound 26 bound 5-HT2 receptors with high affinity (Ki = 2 nM) and >2,000-fold selectivity over 5-HT1C sites, and antagonized DOM's discriminative stimulus effect potently (ED50 = 0.003 mg/kg) without spiperone's disruptive effects. The authors conclude DOM's stimulus is primarily 5-HT2-mediated rather than 5-HT1C-mediated.

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.

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