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σ Receptor Effects of N-Substituted Benztropine Analogs: Implications for Antagonism of Cocaine Self-Administration.
J Pharmacol Exp Ther. 2017 07; 362(1):2-13.JP

Abstract

Several N-substituted benztropine (BZT) analogs are atypical dopamine transport inhibitors as they have affinity for the dopamine transporter (DAT) but have minimal cocaine-like pharmacologic effects and can block numerous effects of cocaine, including its self-administration. Among these compounds, N-methyl (AHN1-055), N-allyl (AHN2-005), and N-butyl (JHW007) analogs of 3α-[bis(4'-fluorophenyl)methoxy]-tropane were more potent in antagonizing self-administration of cocaine and d-methamphetamine than in decreasing food-maintained responding. The antagonism of cocaine self-administration (0.03-1.0 mg/kg per injection) with the above BZT analogs was reproduced in the present study. Further, the stimulant-antagonist effects resembled previously reported effects of pretreatments with combinations of standard DAT inhibitors and σ1-receptor (σ1R) antagonists. Therefore, the present study examined binding of the BZT analogs to σRs, as well as their in vivo σR antagonist effects. Each of the BZT analogs displaced radiolabeled σR ligands with nanomolar affinity. Further, self-administration of the σR agonist DTG (0.1-3.2 mg/kg/injection) was dose dependently blocked by AHN2-005 and JHW007 but potentiated by AHN1-055. In contrast, none of the BZT analogs that were active against DTG self-administration was active against the self-administration of agonists at dopamine D1-like [R(+)-SKF 81297, (±)-SKF 82958 (0.00032-0.01 mg/kg per injection each)], D2-like [R(-)-NPA (0.0001-0.0032 mg/kg per injection), (-)-quinpirole (0.0032-0.1 mg/kg per injection)], or μ-opioid (remifentanil, 0.0001-0.0032 mg/kg per injection) receptors. The present results indicate that behavioral antagonist effects of the N-substituted BZT analogs are specific for abused drugs acting at the DAT and further suggest that σR antagonism contributes to those actions.

Authors+Show Affiliations

Psychobiology Section, Molecular Neuropsychiatry Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health (T.H., T.K., J.L.K.), and Department of Pharmaceutical Sciences, Butler University (W.C.H.), Indianapolis, Indiana.Psychobiology Section, Molecular Neuropsychiatry Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health (T.H., T.K., J.L.K.), and Department of Pharmaceutical Sciences, Butler University (W.C.H.), Indianapolis, Indiana.Psychobiology Section, Molecular Neuropsychiatry Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health (T.H., T.K., J.L.K.), and Department of Pharmaceutical Sciences, Butler University (W.C.H.), Indianapolis, Indiana.Psychobiology Section, Molecular Neuropsychiatry Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health (T.H., T.K., J.L.K.), and Department of Pharmaceutical Sciences, Butler University (W.C.H.), Indianapolis, Indiana jkatz@intra.nida.nih.gov.

Pub Type(s)

Journal Article
Research Support, N.I.H., Intramural

Language

eng

PubMed ID

28442581

Citation

Hiranita, Takato, et al. "Σ Receptor Effects of N-Substituted Benztropine Analogs: Implications for Antagonism of Cocaine Self-Administration." The Journal of Pharmacology and Experimental Therapeutics, vol. 362, no. 1, 2017, pp. 2-13.
Hiranita T, Hong WC, Kopajtic T, et al. Σ Receptor Effects of N-Substituted Benztropine Analogs: Implications for Antagonism of Cocaine Self-Administration. J Pharmacol Exp Ther. 2017;362(1):2-13.
Hiranita, T., Hong, W. C., Kopajtic, T., & Katz, J. L. (2017). Σ Receptor Effects of N-Substituted Benztropine Analogs: Implications for Antagonism of Cocaine Self-Administration. The Journal of Pharmacology and Experimental Therapeutics, 362(1), 2-13. https://doi.org/10.1124/jpet.117.241109
Hiranita T, et al. Σ Receptor Effects of N-Substituted Benztropine Analogs: Implications for Antagonism of Cocaine Self-Administration. J Pharmacol Exp Ther. 2017;362(1):2-13. PubMed PMID: 28442581.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - σ Receptor Effects of N-Substituted Benztropine Analogs: Implications for Antagonism of Cocaine Self-Administration. AU - Hiranita,Takato, AU - Hong,Weimin C, AU - Kopajtic,Theresa, AU - Katz,Jonathan L, Y1 - 2017/04/25/ PY - 2017/03/01/received PY - 2017/04/20/accepted PY - 2017/07/01/pmc-release PY - 2017/4/27/pubmed PY - 2017/6/22/medline PY - 2017/4/27/entrez SP - 2 EP - 13 JF - The Journal of pharmacology and experimental therapeutics JO - J. Pharmacol. Exp. Ther. VL - 362 IS - 1 N2 - Several N-substituted benztropine (BZT) analogs are atypical dopamine transport inhibitors as they have affinity for the dopamine transporter (DAT) but have minimal cocaine-like pharmacologic effects and can block numerous effects of cocaine, including its self-administration. Among these compounds, N-methyl (AHN1-055), N-allyl (AHN2-005), and N-butyl (JHW007) analogs of 3α-[bis(4'-fluorophenyl)methoxy]-tropane were more potent in antagonizing self-administration of cocaine and d-methamphetamine than in decreasing food-maintained responding. The antagonism of cocaine self-administration (0.03-1.0 mg/kg per injection) with the above BZT analogs was reproduced in the present study. Further, the stimulant-antagonist effects resembled previously reported effects of pretreatments with combinations of standard DAT inhibitors and σ1-receptor (σ1R) antagonists. Therefore, the present study examined binding of the BZT analogs to σRs, as well as their in vivo σR antagonist effects. Each of the BZT analogs displaced radiolabeled σR ligands with nanomolar affinity. Further, self-administration of the σR agonist DTG (0.1-3.2 mg/kg/injection) was dose dependently blocked by AHN2-005 and JHW007 but potentiated by AHN1-055. In contrast, none of the BZT analogs that were active against DTG self-administration was active against the self-administration of agonists at dopamine D1-like [R(+)-SKF 81297, (±)-SKF 82958 (0.00032-0.01 mg/kg per injection each)], D2-like [R(-)-NPA (0.0001-0.0032 mg/kg per injection), (-)-quinpirole (0.0032-0.1 mg/kg per injection)], or μ-opioid (remifentanil, 0.0001-0.0032 mg/kg per injection) receptors. The present results indicate that behavioral antagonist effects of the N-substituted BZT analogs are specific for abused drugs acting at the DAT and further suggest that σR antagonism contributes to those actions. SN - 1521-0103 UR - https://www.unboundmedicine.com/medline/citation/28442581/σ_Receptor_Effects_of_N_Substituted_Benztropine_Analogs:_Implications_for_Antagonism_of_Cocaine_Self_Administration_ L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=28442581 DB - PRIME DP - Unbound Medicine ER -