Discovery of a novel nicotinic receptor antagonist for the treatment of nicotine addiction: 1-(3-Picolinium)-12-triethylammonium-dodecane dibromide (TMPD).

Discovery of a novel nicotinic receptor antagonist for the treatment of nicotine addiction: 1-(3-Picolinium)-12-triethylammonium-dodecane dibromide (TMPD). Research Abstract Details 

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Discovery of a novel nicotinic receptor antagonist for the treatment of nicotine addiction: 1-(3-Picolinium)-12-triethylammonium-dodecane dibromide (TMPD). Abstract Text:

Linda P Dwoskin,B Matthew Joyce,Guangrong Zheng,Nichole M Neugebauer,Vamshi K Manda,Paul Lockman,Roger L Papke,Michael T Bardo,Peter A Crooks,

Limitations in efficacy and high relapse rates of currently available smoking cessation agents reveal the need for more efficacious pharmacotherapies. One strategy is to develop subtype-selective nicotinic receptor (nAChR) antagonists that inhibit nicotine-evoked dopamine (DA) release, the primary neurotransmitter involved in nicotine reward. Simple alkylation of the pyridino N-atom converts nicotine from a potent agonist into a potent antagonist. The classical antagonists, hexamethonium and decamethonium, differentiate between peripheral nAChR subtypes. Using a similar approach, we interconnected varying quaternary ammonium moieties with a lipophilic linker to provide N,N'-bis-nicotinium analogs, affording a lead compound, N,N'-dodecyl-1,12-diyl-bis-3-picolinium dibromide (bPiDDB), which inhibited nicotine-evoked DA release and decreased nicotine self-administration. The current work describes a novel compound, 1-(3-picolinium)-12-triethylammonium-dodecane dibromide (TMPD), a hybrid of bPiDDB and decamethonium. TMPD completely inhibited (IC(50)=500 nM) nicotine-evoked DA release from superfused rat striatal slices, suggesting that TMPD acts as a nAChR antagonist at more than one subtype. TMPD (1 microM) inhibited the response to acetylcholine at alpha3beta4, alpha4beta4, alpha4beta2, and alpha1beta1varepsilondelta receptors expressed in Xenopus oocytes. TMPD had a 2-fold higher affinity than choline for the blood-brain barrier choline transporter, suggesting brain bioavailability. TMPD did not inhibit hyperactivity in nicotine sensitized rats, but significantly and specifically decreased nicotine self-administration. Together, the results suggest that TMPD may have the ability to reduce the rewarding effect of nicotine with minimal side effects, a pharmacological profile indicative of potential clinical utility for the treatment of tobacco dependence.

Discovery of a novel nicotinic receptor antagonist for the treatment of nicotine addiction: 1-(3-Picolinium)-12-triethylammonium-dodecane dibromide (TMPD). Publishing Authors By Initials

LP Dwoskin,BM Joyce,G Zheng,NM Neugebauer,VK Manda,P Lockman,RL Papke,MT Bardo,PA Crooks,

For similar disorders of environmental origin: substance-related disorders: tobacco use disorder research abstracts see: disorders of environmental origin: substance-related disorders: tobacco use disorder research

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Discovery of a novel nicotinic receptor antagonist for the treatment of nicotine addiction: 1-(3-Picolinium)-12-triethylammonium-dodecane dibromide (TMPD). Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: Biochemical pharmacology

VOLUME: 74

Page Numbers: 1271-82

Journal Abbreviation: Biochem. Pharmacol.

ISSN: 0006-2952

DAY: 21

MONTH: 07

YEAR: 2007

Discovery of a novel nicotinic receptor antagonist for the treatment of nicotine addiction: 1-(3-Picolinium)-12-triethylammonium-dodecane dibromide (TMPD). Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 101032

Discovery of a novel nicotinic receptor antagonist for the treatment of nicotine addiction: 1-(3-Picolinium)-12-triethylammonium-dodecane dibromide (TMPD). Keywords Mesh Terms:

KEYWORDS: Tobacco Use Disorder

MESH TERMS: drug therapy

Chemical & Substance for Abstract: Discovery of a novel nicotinic receptor antagonist for the treatment of nicotine addiction: 1-(3-Picolinium)-12-triethylammonium-dodecane dibromide (TMPD). Information

Substance Name: Choline

Registry Number: 62-49-7

Grant and Affiliation Information for Discovery of a novel nicotinic receptor antagonist for the treatment of nicotine addiction: 1-(3-Picolinium)-12-triethylammonium-dodecane dibromide (TMPD).

AFFILIATION: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0082, USA. LDwoskin@email.uky.edu

Country: England

AGENCY: United States NIDA

GRANT: DA017548

ACRONYM: DA

MEDLINETA: Biochem Pharmacol

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