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Synthesis and pharmacology of site-specific cocaine abuse treatment agents: 2-(aminomethyl)-3-phenylbicyclo[2.2.2]- and -[2.2.1]alkane dopamine uptake inhibitors.

Abstract
As part of a program to develop site-specific medications for cocaine abuse, a series of 2-(aminomethyl)-3-phenylbicyclo[2.2.2]- and -[2.2.1]alkane derivatives was synthesized and tested for inhibitory potency in [3H]WIN 35,428 binding and [3H]dopamine uptake assays using rat striatal tissue. Selected compounds were tested for their ability to substitute for cocaine in rat drug discrimination tests. Synthesis was accomplished by a series of Diels-Alder reactions, using cis- and trans-cinnamic acid derivatives (nitrile, acid, acid chloride) with cyclohexadiene and cyclopentadiene. Standard manipulations produced the aminomethyl side chain. Many of the compounds bound with high affinity (median IC50 = 223 nM) to the cocaine binding site as marked by [3H]WIN 35,428. Potency in the binding assay was strongly enhanced by chlorine atoms in the 3- and/or 4-position on the aromatic ring and was little affected by corresponding methoxy groups. In the [2.2.2] series there was little difference in potency between cis and trans compounds or between N, N-dimethylamines and primary amines. In the [2.2.1] series the trans exo compounds tended to be least potent against binding, whereas the cis exo compounds were the most potent (4-Cl cis exo: IC50 = 7.7 nM, 27-fold more potent than 4-Cl trans-exo). Although the potencies of the bicyclic derivatives in the binding and uptake assays were highly correlated, some of the compounds were 5-7-fold less potent at inhibiting [3H]dopamine uptake than [3H]WIN 35,428 binding (for comparison, cocaine has a lower discrimination ratio (DR) of 2.5). The DR values were higher for almost all primary amines and for the trans-[2.2.2] series as compared to the cis-[2.2.2]. Most of the compounds had Hill coefficients approaching unity, except for the [2. 2.2] 3,4-dichloro derivatives, which all had nH values of about 2.0. Two of the compounds were shown to fully substitute for cocaine in drug discrimination tests in rats, and one had a very long duration of action.
AuthorsH M Deutsch, D M Collard, L Zhang, K S Burnham, A K Deshpande, S G Holtzman, M M Schweri
JournalJournal of medicinal chemistry (J Med Chem) Vol. 42 Issue 5 Pg. 882-95 (Mar 11 1999) ISSN: 0022-2623 [Print] United States
PMID10072685 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Bridged Bicyclo Compounds
  • Dopamine Uptake Inhibitors
  • (1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester
  • Cocaine
  • Dopamine
Topics
  • Animals
  • Bridged Bicyclo Compounds (chemical synthesis, chemistry, metabolism, pharmacology)
  • Cocaine (analogs & derivatives, metabolism)
  • Cocaine-Related Disorders (drug therapy)
  • Discrimination Learning (drug effects)
  • Dopamine (metabolism)
  • Dopamine Uptake Inhibitors (chemical synthesis, chemistry, metabolism, pharmacology)
  • In Vitro Techniques
  • Male
  • Models, Molecular
  • Neostriatum (metabolism, ultrastructure)
  • Protein Binding
  • Rats
  • Rats, Sprague-Dawley
  • Stereoisomerism
  • Structure-Activity Relationship
  • Synaptosomes (metabolism)

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