Janusz J. Kulagowski

ADVERTISEMENT RETURN TO ISSUEPREVLetterNEXT3-[[4-(4-Chlorophenyl)piperazin-1-yl]methyl]-1H-pyrrolo[2,3-b]pyridine: An Antagonist with High Affinity and Selectivity for the Human Dopamine D4 ReceptorJanusz J. Kulagowski, Howard B. Broughton, Neil R. Curtis, Ian M. Mawer, Mark P. Ridgill, Raymond Baker, Frances Emms, Stephen B. Freedman, Rosemarie Marwood, Shil Patel, Smita Patel, C. Ian Ragan, and Paul D. LeesonView Author Information Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, U.K. Cite this: J. Med. Chem. 1996, 39, 10, 1941–1942Publication Date (Web):May 10, 1996Publication History Received22 January 1996Published online10 May 1996Published inissue 1 January 1996https://doi.org/10.1021/jm9600712Copyright © 1996 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views1285Altmetric-Citations204LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit Read OnlinePDF (105 KB) Get e-AlertsSupporting Info (1)»Supporting Information Supporting Information SUBJECTS:Amines,Antagonists,Indoles,Receptors,Selectivity Get e-Alerts

Dopamine receptor subtypes have been classified generally as D1-like (e.g., D1, D5) or D2-like (D2, D3, D4), and converging evidence suggests that D2-like receptors may be especially important in mediating the abuse-related effects of cocaine. However, it has been difficult to differentiate the roles of the D2-like receptor subtypes in the behavioral effects of cocaine because of the relatively low selectivity of drugs for D2, D3, and D4 receptors in vivo. The goal of the present series of studies was to investigate the contributions of D2-like receptor subtypes in the reinforcing effects of cocaine using new genetic and pharmacological tools. First, we evaluated cocaine self-administration behavior, and related effects of nonselective D2-like drugs, in mutant mice that lack the D2 receptor but express D3 and D4 receptors. When high doses of cocaine on the descending limb of the cocaine dose-effect function were available, D2 mutant mice self-administered at higher rates than their heterozygous or wild-type littermates, but the ascending limb of the cocaine dose-effect function did not differ between genotypes. Elevated rates of drug intake were not attributable to nonspecific increases in response rate, because response rates maintained by presentation of a range of food concentrations were significantly lower in D2 mutant mice than in wild-type mice. In wild-type mice, pretreatment with the D2-like antagonist eticlopride increased rates of self-administration of high doses of cocaine, and the D2-like agonist quinelorane served as a positive reinforcer when substituted for cocaine. However, these effects of eticlopride and quinelorane were not observed in mice that lacked the D2 receptor. Next, we compared the effects of novel antagonists selective for different D2 receptor subtypes on cocaine self-administration behavior in outbred rats. In rats, a D2 selective antagonist increased rates of self-administration of high doses of cocaine and also combinations of cocaine and the D2-like agonist quinelorane, whereas D3/D4 antagonists were ineffective. Collectively, these findings suggest that the D2 receptor is not necessary for cocaine self-administration, but this receptor subtype is involved in mechanisms that limit rates of high-dose cocaine self-administration. Our results also suggest that D3 and D4 receptors do not play major roles in the modulation of cocaine self-administration by D2-like drugs.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXT3'-(Arylmethyl)- and 3'-(Aryloxy)-3-phenyl-4-hydroxyquinolin- 2(1H)-ones: Orally Active Antagonists of the Glycine Site on the NMDA ReceptorJanusz J. Kulagowski, Raymond Baker, Neil R. Curtis, Ian M. Mawer, Angela M. Moseley, Mark P. Ridgill, Michael Rowley, Ian Stansfield, Paul D. Leeson, and Cite this: J. Med. Chem. 1994, 37, 10, 1402–1405Publication Date (Print):May 1, 1994Publication History Published online1 May 2002Published inissue 1 May 1994https://pubs.acs.org/doi/10.1021/jm00036a002https://doi.org/10.1021/jm00036a002research-articleACS PublicationsRequest reuse permissionsArticle Views546Altmetric-Citations118LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts