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N-substituted benztropine analogs: selective dopamine transporter ligands with a fast onset of action and minimal cocaine-like behavioral effects.
J Pharmacol Exp Ther. 2011 Feb; 336(2):575-85.JP

Abstract

Previous studies suggested that differences between the behavioral effects of cocaine and analogs of benztropine were related to the relatively slow onset of action of the latter compounds. Several N-substituted benztropine analogs with a relatively fast onset of effects were studied to assess whether a fast onset of effects would render the effects more similar to those of cocaine. Only one of the compounds increased locomotor activity, and the increases were modest compared with those of 10 to 20 mg/kg cocaine. In rats trained to discriminate 10 mg/kg cocaine from saline none of the compounds produced more than 40% cocaine-like responds up to 2 h after injection. None of the compounds produced place-conditioning when examined up to 90 min after injection, indicating minimal abuse liability. The compounds had 5.6 to 30 nM affinities at the dopamine transporter (DAT), with uniformly lower affinities at norepinephrine and serotonin transporters (from 490-4600 and 1420-7350 nM, respectively). Affinities at muscarinic M(1) receptors were from 100- to 300-fold lower than DAT affinities, suggesting minimal contribution of those sites to the behavioral effects of the compounds. Affinities at histaminic H(1) sites were from 11- to 43-fold lower than those for the DAT. The compounds also had affinity for sigma, 5-hydroxytryptamine(1) (5-HT(1)), and 5-HT(2) receptors that may have contributed to their behavioral effects. Together, the results indicate that a slow onset of action is not a necessary condition for reduced cocaine-like effects of atypical DAT ligands and suggest several mechanisms that may contribute to the reduced cocaine-like efficacy of these compounds.

Authors+Show Affiliations

Sections, Medications Discovery Research Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, Maryland 21224, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

21088247

Citation

Li, Su-Min, et al. "N-substituted Benztropine Analogs: Selective Dopamine Transporter Ligands With a Fast Onset of Action and Minimal Cocaine-like Behavioral Effects." The Journal of Pharmacology and Experimental Therapeutics, vol. 336, no. 2, 2011, pp. 575-85.
Li SM, Kopajtic TA, O'Callaghan MJ, et al. N-substituted benztropine analogs: selective dopamine transporter ligands with a fast onset of action and minimal cocaine-like behavioral effects. J Pharmacol Exp Ther. 2011;336(2):575-85.
Li, S. M., Kopajtic, T. A., O'Callaghan, M. J., Agoston, G. E., Cao, J., Newman, A. H., & Katz, J. L. (2011). N-substituted benztropine analogs: selective dopamine transporter ligands with a fast onset of action and minimal cocaine-like behavioral effects. The Journal of Pharmacology and Experimental Therapeutics, 336(2), 575-85. https://doi.org/10.1124/jpet.110.173260
Li SM, et al. N-substituted Benztropine Analogs: Selective Dopamine Transporter Ligands With a Fast Onset of Action and Minimal Cocaine-like Behavioral Effects. J Pharmacol Exp Ther. 2011;336(2):575-85. PubMed PMID: 21088247.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - N-substituted benztropine analogs: selective dopamine transporter ligands with a fast onset of action and minimal cocaine-like behavioral effects. AU - Li,Su-Min, AU - Kopajtic,Theresa A, AU - O'Callaghan,Matthew J, AU - Agoston,Gregory E, AU - Cao,Jianjing, AU - Newman,Amy Hauck, AU - Katz,Jonathan L, Y1 - 2010/11/18/ PY - 2010/11/20/entrez PY - 2010/11/23/pubmed PY - 2011/3/4/medline SP - 575 EP - 85 JF - The Journal of pharmacology and experimental therapeutics JO - J. Pharmacol. Exp. Ther. VL - 336 IS - 2 N2 - Previous studies suggested that differences between the behavioral effects of cocaine and analogs of benztropine were related to the relatively slow onset of action of the latter compounds. Several N-substituted benztropine analogs with a relatively fast onset of effects were studied to assess whether a fast onset of effects would render the effects more similar to those of cocaine. Only one of the compounds increased locomotor activity, and the increases were modest compared with those of 10 to 20 mg/kg cocaine. In rats trained to discriminate 10 mg/kg cocaine from saline none of the compounds produced more than 40% cocaine-like responds up to 2 h after injection. None of the compounds produced place-conditioning when examined up to 90 min after injection, indicating minimal abuse liability. The compounds had 5.6 to 30 nM affinities at the dopamine transporter (DAT), with uniformly lower affinities at norepinephrine and serotonin transporters (from 490-4600 and 1420-7350 nM, respectively). Affinities at muscarinic M(1) receptors were from 100- to 300-fold lower than DAT affinities, suggesting minimal contribution of those sites to the behavioral effects of the compounds. Affinities at histaminic H(1) sites were from 11- to 43-fold lower than those for the DAT. The compounds also had affinity for sigma, 5-hydroxytryptamine(1) (5-HT(1)), and 5-HT(2) receptors that may have contributed to their behavioral effects. Together, the results indicate that a slow onset of action is not a necessary condition for reduced cocaine-like effects of atypical DAT ligands and suggest several mechanisms that may contribute to the reduced cocaine-like efficacy of these compounds. SN - 1521-0103 UR - https://www.unboundmedicine.com/medline/citation/21088247/N_substituted_benztropine_analogs:_selective_dopamine_transporter_ligands_with_a_fast_onset_of_action_and_minimal_cocaine_like_behavioral_effects_ L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=21088247 DB - PRIME DP - Unbound Medicine ER -