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Development of Drugs with Dual Dopamine Transporter and Sigma 1 Receptor Activity
Author(s) -
Kopajtic Theresa,
Cao Jianjing,
Hiranita Takato,
Tanda Gianluigi,
Newman Amy H.,
Katz Jonathan L
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.745.5
Subject(s) - dopamine transporter , chemistry , antagonist , sigma receptor , stereochemistry , dopamine , receptor , in vivo , transporter , pharmacology , biochemistry , medicine , biology , microbiology and biotechnology , gene
Prior results suggest that rimcazole and its analogues decrease cocaine self administration (SA) through actions mediated by antagonist effects at sigma 1 receptors (σ 1 Rs) along with blockade of the dopamine transporter (DAT). The present study compared several analogues of rimcazole for the optimum ratio of σ 1 R to DAT affinity for effects on cocaine SA. SH‐324, which had a 2‐fold σ 1 R/DAT affinity ratio, was approximately 3‐fold more potent than rimcazole and SH‐328 in attenuating cocaine SA. The latter two compounds had respective σ 1 R/DAT affinity ratios of 9.14 and 0.11, suggesting that the optimum ratio lies between those values. Rimcazole analogues with varying affinities and selectivities for DAT and σ 1 Rs were prepared (Cao et al. 2003; 2008). The hydroxylated linking chain analogue, JJC 2‐010 [(±)3‐(4‐(3‐(bis(4‐fluorophenyl)amino)propyl)piperazin‐1‐yl)‐1‐phenylpropan‐1‐ol], and its N‐benzyl analogue, JJC 2‐006, had a σ 1 R/DAT affinity ratios of 13.04 and 0.27, respectively. Ester analogues of JJC 2‐010 were prepared which had σ 1 R/DAT affinity ratios varying from 16.34 to 0.86. In contrast to rimcazole, these novel compounds had high affinity for the DAT ranging from 1.72 to 51.3 nM, and affinity for σ 1 Rs ranging from 24.9 to 292 nM. Selected compounds with a range of σ 1 R/DAT affinity ratios will be tested for their cocaine antagonist effects in various in vivo procedures indicative of abuse liability.