3'-Fluoro substitution in the pyridine ring of epibatidine improves selectivity and efficacy for alpha4beta2 versus alpha3beta4 nAChRs.
The analog of epibatidine having a fluoro substituent at the 3' position of the pyridine ring has been recently developed and shown to possess binding affinity in the pM range to alpha4beta2 nAChRs and in the nM range to alpha7 nAChRs and to exhibit potent agonist activity in nicotine-induced analgesia tests. Here we used patch-clamp technique in a whole-cell configuration to compare functional activity of 3'-fluoroepibatidine to that of epibatidine by itself on recombinant alpha4beta2, alpha7 and alpha3beta4 neuronal nAChRs. The agonist effect of (+/-)-epibatidine was partial and yielded comparable EC50s of 0.012 microM (72% efficacy) and 0.027 microM (81% efficacy) at alpha4beta2 and alpha3beta4 nAChRs, respectively, but was full at alpha7 nAChRs with an EC50 of 4.8 muM. Testing of the analog at different concentrations revealed that it acts as a full agonist with an EC50 of 0.36 microM at alpha4beta2 nAChRs and induces partial agonist effect (66% efficacy) at alpha7 nAChRs with an EC50 of 9.8 microM and an IC50 corresponding to 225 microM. In contrast, the analog caused only 24% maximal activation at the range of concentrations from 0.1 to 100 microM and, in addition, induced an inhibition of alpha3beta4 nAChR function with an IC50 of 8.3 microM. Our functional data, which are in agreement with previous binding and behavioral findings, demonstrate that 3'-fluoro substitution in the pyridine ring of epibatidine results in an improved pharmacological profile as observed by an increased efficacy and selectivity for alpha4beta2 versus alpha3beta4 nAChRs.
Abdrakhmanova
Galya R
GR
Department of Pharmacology and Toxicology (G.R.A., M.I.D., B.R.M.), Virginia Commonwealth University, Richmond, VA 23298, United States. gabdrakhmano@vcu.edu
Carroll
F Ivy
FI
Damaj
M I
MI
Martin
Billy R
BR
D000109:Acetylcholine / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry* / Q000494:pharmacology; D002461:Cell Line, Transformed; D004079:Dihydro-beta-Erythroidine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D018722:Nicotinic Agonists / Q000737:chemistry* / Q000494:pharmacology; D018408:Patch-Clamp Techniques / Q000379:methods; D011725:Pyridines / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014162:Transfection
D019086:Bridged Bicyclo Compounds, Heterocyclic; D018722:Nicotinic Agonists; D011725:Pyridines; D011978:Receptors, Nicotinic; C403530:nicotinic receptor alpha3beta4; C403531:nicotinic receptor alpha4beta2; D004079:Dihydro-beta-Erythroidine; C082748:epibatidine; D000109:Acetylcholine; C023666:pyridine
Acta Pharmacol Sin. 2008 Mar;29(3):305-19
18298895
Mol Pharmacol. 2006 Aug;70(2):755-68
16720757
Annu Rev Pharmacol Toxicol. 2007;47:699-729
17009926
Neuroscience. 2002;109(4):757-65
11927157
J Neurosci. 1996 Dec 15;16(24):7892-901
8987817
Bioorg Med Chem Lett. 2004 Apr 19;14(8):1889-96
15050621
Proc West Pharmacol Soc. 1995;38:127-30
7480004
J Neurophysiol. 2007 Dec;98(6):3388-96
17942622
Neuropharmacology. 1999 Jun;38(6):769-83
10465681
Trends Pharmacol Sci. 2006 Sep;27(9):482-91
16876883
Recept Channels. 2001;7(6):491-6
11918351
Mol Pharmacol. 2005 Dec;68(6):1669-77
16129734
Nat Prod Rep. 2000 Apr;17(2):131-5
10821107
Mol Pharmacol. 2001 Sep;60(3):568-76
11502889
J Neurobiol. 2002 Dec;53(4):568-79
12436421
J Neurosci. 2003 Apr 15;23(8):3176-85
12716925
Mol Pharmacol. 1998 Aug;54(2):322-33
9687574
Neuropharmacology. 2000 Oct;39(13):2561-9
11044727
J Biol Chem. 2004 Sep 3;279(36):37842-51
15234980
Mol Pharmacol. 2003 Mar;63(3):574-80
12606764
Bioorg Med Chem Lett. 2005 Oct 1;15(19):4385-8
16039849
Nature. 1999 Apr 29;398(6730):805-10
10235262
Mol Pharmacol. 1999 Jun;55(6):970-81
10347237
Mol Pharmacol. 2008 Aug;74(2):348-59
18445710
J Mol Neurosci. 2006;30(1-2):15-6
17192608
Mol Pharmacol. 1992 Jan;41(1):31-7
1732720
Proc Natl Acad Sci U S A. 1987 Jan;84(2):595-9
3467376
Chem Biol. 2000 Jul;7(7):545-55
10903939
Behav Brain Res. 2000 Aug;113(1-2):131-41
10942040
Curr Pharm Des. 2006;12(4):407-28
16472136
Mol Pharmacol. 2006 Jun;69(6):1945-52
16505153
ChemMedChem. 2007 Jun;2(6):746-67
17295372
Nature. 1995 Mar 2;374(6517):65-7
7870173
Mol Pharmacol. 2002 Feb;61(2):369-78
11809862
Neuropharmacology. 2000 Oct;39(13):2785-91
11044748
Front Biosci. 2008 Jan 01;13:492-504
17981563
J Med Chem. 2001 Nov 22;44(24):4039-41
11708907
J Neurochem. 2002 Aug;82(3):468-81
12153472
J Med Chem. 2002 Oct 10;45(21):4755-61
12361403
Biochim Biophys Acta. 2008 Apr;1778(4):864-71
18249185
J Med Chem. 2005 Mar 24;48(6):1721-4
15771418
Mol Pharmacol. 1994 Apr;45(4):563-9
8183234
J Neurophysiol. 2001 Oct;86(4):1773-82
11600638
Mol Pharmacol. 2003 Dec;64(6):1283-94
14645658
Anal Chem. 2008 Jan 1;80(1):48-54
18062706
Proc Natl Acad Sci U S A. 2001 Apr 10;98(8):4734-9
11274373
J Pharmacol Exp Ther. 2002 Sep;302(3):1246-52
12183686