title: Discovery of a novel nicotinic receptor antagonist for the treatment of nicotine addiction: 1-(3-Picolinium)-12-triethylammonium-dodecane dibromide (TMPD).
abstract: 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.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0082, USA. LDwoskin@email.uky.edu
authors.forename: Linda P
authors.initials: LP
authors.lastname: Dwoskin
authors.forename: B Matthew
authors.initials: BM
authors.lastname: Joyce
authors.forename: Guangrong
authors.initials: G
authors.lastname: Zheng
authors.forename: Nichole M
authors.initials: NM
authors.lastname: Neugebauer
authors.forename: Vamshi K
authors.initials: VK
authors.lastname: Manda
authors.forename: Paul
authors.initials: P
authors.lastname: Lockman
authors.forename: Roger L
authors.initials: RL
authors.lastname: Papke
authors.forename: Michael T
authors.initials: MT
authors.lastname: Bardo
authors.forename: Peter A
authors.initials: PA
authors.lastname: Crooks
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier; D002794:Choline / Q000493:pharmacokinetics; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D008297:Male; D018733:Nicotinic Antagonists / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010847:Picolines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D014029:Tobacco Use Disorder / Q000188:drug therapy*
chemical_list: C524030:1-(3-picolinium)-12-triethylammonium-dodecane dibromide; D018733:Nicotinic Antagonists; D010847:Picolines; D002794:Choline; D004298:Dopamine