title: Differential modulation of brain nicotinic acetylcholine receptor function by cytisine, varenicline, and two novel bispidine compounds: emergent properties of a hybrid molecule.
abstract: Partial agonist therapies for the treatment of nicotine addiction and dependence depend on both agonistic and antagonistic effects of the ligands, and side effects associated with other nAChRs greatly limit the efficacy of nicotinic partial agonists. We evaluated the in vitro pharmacological properties of four partial agonists, two current smoking cessation drugs, varenicline and cytisine, and two novel bispidine compounds, BPC and BMSP, by using defined nAChR subtypes expressed in Xenopus laevis oocytes and human embryonic kidney 293 cells. Similar to varenicline and cytisine, BPC and BMSP are partial agonists of α4β2 nAChRs, although BMSP produced very little activation of these receptors. Unlike varenicline and cytisine, BPC and BMSP showed desired low activity. BPC produced mecamylamine-sensitive steady-state activation of α4* receptors that was not evident with BMSP. We evaluated the modulation of α4*- and α7-mediated responses in rat lateral geniculate nucleus (LGN) neurons and hippocampal stratum radiatum (SR) interneurons, respectively. The LGN neurons were sensitive to a very low concentration of varenicline, and the SR interneuron responses were also sensitive to varenicline at a submicromolar concentration. Although 300 nM BPC strongly inhibited the ACh-evoked responses of LGN neurons, it did not inhibit the α7 currents of SR interneurons. Similar results were observed with 300 nM BMSP. Additionally, the bispidine compounds were efficacious in the mouse tail suspension test, demonstrating that they affect receptors in the brain when delivered systemically. Our data indicate that BPC and BMSP are promising α4β2* partial agonists for pharmacotherapeutics.
authors: Department of Pharmacology and Therapeutics, College of Medicine, University of Florida, Gainesville, Florida (C.P., C.S., C.T., R.L.P.); Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut (Y.S.M., M.R.P.); and Department of Pharmaceutical Sciences, College of Pharmacy, University of Hawaii, Hilo, Hawaii (C.E., I.T., D.G.).
authors: Can
authors: C
authors: Peng
authors: Clare
authors: C
authors: Stokes
authors: Yann S
authors: YS
authors: Mineur
authors: Marina R
authors: MR
authors: Picciotto
authors: Chengju
authors: C
authors: Tian
authors: Christoph
authors: C
authors: Eibl
authors: Isabelle
authors: I
authors: Tomassoli
authors: Daniela
authors: D
authors: Guendisch
authors: Roger L
authors: RL
authors: Papke
mesh_terms: D000470:Alkaloids / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001392:Azocines / Q000737:chemistry / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001552:Benzazepines / Q000737:chemistry / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D054333:Drug Partial Agonism; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D015394:Molecular Structure; D018722:Nicotinic Agonists / Q000737:chemistry / Q000494:pharmacology*; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011807:Quinolizines / Q000737:chemistry / Q000494:pharmacology; D011810:Quinoxalines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism*; D014029:Tobacco Use Disorder / Q000188:drug therapy / Q000378:metabolism / Q000523:psychology; D000068580:Varenicline; D014982:Xenopus laevis; D000093843:Quinolizidine Alkaloids
chemical_list: D000470:Alkaloids; D001392:Azocines; D001552:Benzazepines; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018722:Nicotinic Agonists; D011807:Quinolizines; D011810:Quinoxalines; D011978:Receptors, Nicotinic; D000068580:Varenicline; C495809:bispidine; C004712:cytisine; D000093843:Quinolizidine Alkaloids
references: J Pharmacol Exp Ther. 2011 May;337(2):367-79
references: 21285282
references: Mol Pharmacol. 2012 Oct;82(4):746-59
references: 22828799
references: Neuropharmacology. 2009 Jan;56(1):237-46
references: 18723036
references: AAPS J. 2009 Mar;11(1):167-77
references: 19280351
references: PLoS One. 2011;6(11):e27016
references: 22073240
references: Am J Ther. 2013 May-Jun;20(3):235-46
references: 23615317
references: Mol Pharmacol. 2008 Jul;74(1):132-43
references: 18381563
references: Br J Pharmacol. 2013 Feb;168(4):835-49
references: 22957729
references: J Neurosci. 2008 Nov 19;28(47):12318-27
references: 19020025
references: Eur J Pharmacol. 2009 Mar 1;605(1-3):114-6
references: 19168054
references: J Med Chem. 2009 Jul 23;52(14):4345-57
references: 19548687
references: Curr Psychiatry Rep. 2012 Oct;14(5):478-85
references: 22821177
references: J Neurosci. 2010 Apr 14;30(15):5311-25
references: 20392953
references: J Pharmacol Exp Ther. 2009 Apr;329(1):377-86
references: 19164465
references: Neuron. 2002 Mar 14;33(6):905-19
references: 11906697
references: Neuropharmacology. 2013 Jul;70:228-35
references: 23416040
references: Mol Pharmacol. 1994 Jan;45(1):142-9
references: 8302273
references: Mol Pharmacol. 2011 Jan;79(1):126-40
references: 20923852
references: Neuropharmacology. 2012 Sep;63(4):538-46
references: 22580377
references: Methods. 2010 May;51(1):121-33
references: 20085813
references: J Pharmacol Exp Ther. 2002 May;301(2):651-60
references: 11961070
references: J Neurosci. 2011 Jul 27;31(30):10891-902
references: 21795541
references: Acc Chem Res. 2008 Jan;41(1):69-77
references: 17665872
references: Trends Pharmacol Sci. 2010 Dec;31(12):580-6
references: 20965579
references: J Neurosci. 2003 Oct 8;23(27):9004-15
references: 14534234
references: Br J Pharmacol. 2002 Sep;137(1):49-61
references: 12183330
references: Neuropharmacology. 2007 Apr;52(5):1256-62
references: 17320916
references: Neuropharmacology. 2009 Mar;56(4):821-30
references: 19705574
references: Neuron. 2011 May 12;70(3):522-35
references: 21555077
references: J Biol Chem. 2003 Sep 5;278(36):34411-7
references: 12821669
references: Neuropsychopharmacology. 2012 Apr;37(5):1134-43
references: 22169946
references: Neuropharmacology. 2007 Jul;53(1):134-44
references: 17544457
references: J Gen Intern Med. 2009 May;24(5):563-9
references: 19238488
references: Cold Spring Harb Perspect Med. 2013 Jan 01;3(1):a012112
references: 23143843
references: J Clin Psychiatry. 2009 Jul;70(7):1026-31
references: 19323966
references: Neuropsychopharmacology. 2010 Feb;35(3):665-73
references: 19890263
references: J Dual Diagn. 2007 Nov 1;3(3-4):43-59
references: 19122786
references: Mol Pharmacol. 2006 Sep;70(3):801-5
references: 16766716