Tags

Type your tag names separated by a space and hit enter

Effects of N-substituted analogs of benztropine: diminished cocaine-like effects in dopamine transporter ligands.
J Pharmacol Exp Ther. 2004 May; 309(2):650-60.JP

Abstract

Previous studies demonstrated that analogs of benztropine (BZT) possess high affinity for the dopamine transporter, inhibit dopamine uptake, but generally have behavioral effects different from those of cocaine. One hypothesis is that muscarinic-M(1) receptor actions interfere with cocaine-like effects. Several tropane-nitrogen substitutions of 4',4"-diF-BZT have reduced M(1) affinity compared with the CH(3)-analog (AHN 1-055; 3alpha-[bis-(4-fluorophenyl)methoxy]tropane). All of the compounds displaced [(3)H]WIN 35,428 (2beta-carbomethoxy-3beta-(4-fluorophenyl)tropane) binding with affinities ranging from 11 to 108 nM. Affinities at norepinephrine ([(3)H]nisoxetine) and serotonin ([(3)H]citalopram) transporters ranged from 457 to 4810 and 376 to 3260 nM, respectively, and at muscarinic M(1) receptors ([(3)H]pirenzepine) from 11.6 (AHN 1-055) to higher values, reaching 1030 nM for the other BZT-analogs. Cocaine and AHN 1-055 produced dose-related increases in locomotor activity in mice, with AHN 1-055 less effective than cocaine. The other compounds were ineffective in stimulating activity. In rats discriminating cocaine (29 micromol/kg i.p.) from saline, WIN 35,428 fully substituted for cocaine, whereas AHN 1-055 produced a maximal substitution of 79%. None of the other analogs fully substituted for cocaine. WIN 35,428 produced dose-related leftward shifts in the cocaine dose-effect curve, whereas selected BZT analogs produced minimal changes in the effects of cocaine. The results suggest that reducing M(1) affinity of 4',4"-diF-BZT with N-substitutions reduces effectiveness in potentiating the effects of cocaine. Furthermore, although the BZT-analogs bind with high affinity at the dopamine transporter, their behavioral effects differ from those of cocaine. These compounds have reduced efficacy compared with cocaine, a long duration of action, and may serve as leads for the development of medications to treat cocaine abuse.

Authors+Show Affiliations

Psychobiology, Medications Discovery Research Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA. jkatz@intra.nida.nih.govNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

14755006

Citation

Katz, Jonathan L., et al. "Effects of N-substituted Analogs of Benztropine: Diminished Cocaine-like Effects in Dopamine Transporter Ligands." The Journal of Pharmacology and Experimental Therapeutics, vol. 309, no. 2, 2004, pp. 650-60.
Katz JL, Kopajtic TA, Agoston GE, et al. Effects of N-substituted analogs of benztropine: diminished cocaine-like effects in dopamine transporter ligands. J Pharmacol Exp Ther. 2004;309(2):650-60.
Katz, J. L., Kopajtic, T. A., Agoston, G. E., & Newman, A. H. (2004). Effects of N-substituted analogs of benztropine: diminished cocaine-like effects in dopamine transporter ligands. The Journal of Pharmacology and Experimental Therapeutics, 309(2), 650-60.
Katz JL, et al. Effects of N-substituted Analogs of Benztropine: Diminished Cocaine-like Effects in Dopamine Transporter Ligands. J Pharmacol Exp Ther. 2004;309(2):650-60. PubMed PMID: 14755006.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effects of N-substituted analogs of benztropine: diminished cocaine-like effects in dopamine transporter ligands. AU - Katz,Jonathan L, AU - Kopajtic,Theresa A, AU - Agoston,Gregory E, AU - Newman,Amy Hauck, Y1 - 2004/01/30/ PY - 2004/2/3/pubmed PY - 2004/6/23/medline PY - 2004/2/3/entrez SP - 650 EP - 60 JF - The Journal of pharmacology and experimental therapeutics JO - J. Pharmacol. Exp. Ther. VL - 309 IS - 2 N2 - Previous studies demonstrated that analogs of benztropine (BZT) possess high affinity for the dopamine transporter, inhibit dopamine uptake, but generally have behavioral effects different from those of cocaine. One hypothesis is that muscarinic-M(1) receptor actions interfere with cocaine-like effects. Several tropane-nitrogen substitutions of 4',4"-diF-BZT have reduced M(1) affinity compared with the CH(3)-analog (AHN 1-055; 3alpha-[bis-(4-fluorophenyl)methoxy]tropane). All of the compounds displaced [(3)H]WIN 35,428 (2beta-carbomethoxy-3beta-(4-fluorophenyl)tropane) binding with affinities ranging from 11 to 108 nM. Affinities at norepinephrine ([(3)H]nisoxetine) and serotonin ([(3)H]citalopram) transporters ranged from 457 to 4810 and 376 to 3260 nM, respectively, and at muscarinic M(1) receptors ([(3)H]pirenzepine) from 11.6 (AHN 1-055) to higher values, reaching 1030 nM for the other BZT-analogs. Cocaine and AHN 1-055 produced dose-related increases in locomotor activity in mice, with AHN 1-055 less effective than cocaine. The other compounds were ineffective in stimulating activity. In rats discriminating cocaine (29 micromol/kg i.p.) from saline, WIN 35,428 fully substituted for cocaine, whereas AHN 1-055 produced a maximal substitution of 79%. None of the other analogs fully substituted for cocaine. WIN 35,428 produced dose-related leftward shifts in the cocaine dose-effect curve, whereas selected BZT analogs produced minimal changes in the effects of cocaine. The results suggest that reducing M(1) affinity of 4',4"-diF-BZT with N-substitutions reduces effectiveness in potentiating the effects of cocaine. Furthermore, although the BZT-analogs bind with high affinity at the dopamine transporter, their behavioral effects differ from those of cocaine. These compounds have reduced efficacy compared with cocaine, a long duration of action, and may serve as leads for the development of medications to treat cocaine abuse. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/14755006/Effects_of_N_substituted_analogs_of_benztropine:_diminished_cocaine_like_effects_in_dopamine_transporter_ligands_ L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=14755006 DB - PRIME DP - Unbound Medicine ER -