Novel bis-2,2,6,6-tetramethylpiperidine (bis-TMP) and bis-mecamylamine antagonists at neuronal nicotinic receptors mediating nicotine-evoked dopamine release

Zhenfa Zhang, Marharyta Pivavarchyk, Karunai Leela Subramanian, A. Gabriela Deaciuc, Linda P. Dwoskin, Peter A. Crooks

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

By linking two or three mecamylamine or 2,2,6,6-tetramethylpiperidine (TMP) molecules together via a linear lipophilic bis-methylene linker or a specially designed conformationally restricted tris-linker, a series of bis- and tris-tertiary amine analogs has been synthesized and evaluated as potent antagonists at nAChRs mediating nicotine-evoked [3H]dopamine release from rat striatal slices. Compounds 7e, 14b and 16 demonstrated high potency in decreasing nicotine-evoked [3H]dopamine release (IC50 = 2.2, 46, and 107 nM, respectively). The preliminary structure-activity data obtained with these new analogs suggest the importance of the length of the methylene linker in the bis-analog series. Such bis-tertiary amino analogs may provide a new strategy for the design of drugable ligands that have high inhibitory potency against nAChRs mediating nicotine-evoked dopamine release in striatum, which have been suggested to be target receptors of interest in the development of potential smoking cessation therapies.

Original languageEnglish
Pages (from-to)1420-1423
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume20
Issue number4
DOIs
StatePublished - Feb 15 2010

Bibliographical note

Funding Information:
This work was supported by NIH/NIDA Grant U19 DA017548 .

Keywords

  • Dopamine release
  • Nicotine addiction
  • Nicotinic acetylcholine receptor
  • Quaternary ammonium

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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