7347-72-0Relevant academic research and scientific papers
Antagonism of 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane stimulus with a newly identified 5-HT2- versus 5-HT(1C)-selective antagonist
Ismaiel,De los Angeles,Teitler,Ingher,Glennon
, p. 2519 - 2525 (1993)
DOM [i.e., 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane] is a 5- HT(1C/2) serotonin agonist that exerts stimulus control of behavior in animals. In order to determine if the discriminative stimulus effect of DOM is 5-HT(1C)- or 5-HT2-mediated, it would be informative to conduct tests of stimulus antagonism with a 5-HT(1C)- or 5-HT2-selective antagonist. To date, no such agents exist. Although the neuroleptic agent spiperone binds at D2 dopamine receptors and 5-HT(1A) serotonin receptors, (a) it displays about a 1000-fold selectivity for 5-HT2 versus 5-HT(1C) 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]decan-4-one (26), was shown to bind at 5-HT2 sites with high affinity (K(i) = 2 nM) and >2,000- fold selectivity versus 5-HT(1C) 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-HT(1C)-mediated, phenomenon, and (b) compound 26 may find application in other pharmacologic investigations where spiperone may not be a suitable antagonist.
Carboxylic acid bioisosteres acylsulfonamides, acylsulfamides, and sulfonylureas as novel antagonists of the CXCR2 receptor
Winters, Michael P.,Crysler, Carl,Subasinghe, Nalin,Ryan, Declan,Leong, Lynette,Zhao, Shuyuan,Donatelli, Robert,Yurkow, Edward,Mazzulla, Marie,Boczon, Lisa,Manthey, Carl L.,Molloy, Christopher,Raymond, Holly,Murray, Lynne,McAlonan, Laura,Tomczuk, Bruce
, p. 1926 - 1930 (2008/12/22)
A series of novel acylsulfonamide, acylsulfamide, and sulfonylurea bioisosteres of carboxylic acids were prepared as CXCR2 antagonists. Structure-activity relationships are reported for these series. One potent orally bioavailable inhibitor had excellent PK properties and was active in a lung injury model in hyperoxia-exposed newborn rats.
