Synthesis and ligand binding of η6-(2β-carbomethoxy-3β-phenyltropane) transition metal complexes

Blake Aronson, Jennifer L. Enmon, Sari Izenwasser, Jonathan L. Katz, Shreekrishna V. Kelkar, Lubin Luo, Steven P. Nolan, Mark L. Trudell

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Abstract

The transition metal complexes [η6-(2β-carbomethoxy-3β- phenyltropane)]tricarbonylchromium (3) and [η6-(2β-carbomethoxy-3β- phenyltropane)][η5-(pentamethylcyclopentadienyl)]ruthenium(II) triflate (4) were synthesized from 2β-carbomethoxy-3β-phenyltropane (2, WIN 35,065) to further elucidate the influence of substituents on the 3β-aryl on the affinity of the ligand for cocaine-binding sites at the dopamine transporter. The compounds were tested for their ability to displace bound [3H]WIN 35,428 (5) from rat caudate putamen tissue and for their ability to inhibit [3H]dopamine uptake. The binding affinity for 3 was 2-fold greater than those observed for cocaine (1) and 2, while the binding affinity for 4 was found to be 100-fold less than those of 1 and 2. In addition, 3 was equipotent with 1 and 2 in [3H]dopamine uptake inhibition studies, while 4 was 10-fold less potent. The potencies of the complexes 3 and 4 correlated well with the structure-activity relationships of other 2β-carbomethoxy- 3β-aryltropane derivatives. These data further support a pharmacophore model in which the region occupied by the aryl ring is a lipophilic pocket with electropositive character.

Original languageEnglish (US)
Pages (from-to)1560-1563
Number of pages4
JournalJournal of Medicinal Chemistry
Volume39
Issue number7
DOIs
StatePublished - Mar 29 1996

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Aronson, B., Enmon, J. L., Izenwasser, S., Katz, J. L., Kelkar, S. V., Luo, L., Nolan, S. P., & Trudell, M. L. (1996). Synthesis and ligand binding of η6-(2β-carbomethoxy-3β-phenyltropane) transition metal complexes. Journal of Medicinal Chemistry, 39(7), 1560-1563. https://doi.org/10.1021/jm9508797