title: From α4β2 Nicotinic Ligands to the Discovery of σ1 Receptor Ligands: Pharmacophore Analysis and Rational Design.
abstract: Comparative analyses of the pharmacophoric elements required for σ1 and nicotinic ligands led to the identification of a potent and selective σ1 ligand (15). Compound15displayed high selectivity for the σ1 receptor (Ki, σ1 = 4.1 nM,Ki, σ2 = 1312 nM) with moderate binding affinity for the DAT (Ki= 373 nM) and NET (Ki= 203 nM) in the PDSP broad screening panel of common CNS neurotransmitter transporters and receptors. The key finding in this present work is that a subtle structural modifica tion could be used as a tool to switch a ligand's selectivity between nAChRs and sigma receptors.
authors: Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United States.
authors: Li-Fang
authors: LF
authors: Yu
authors: Han-Kun
authors: HK
authors: Zhang
authors: Hendra
authors: H
authors: Gunosewoyo
authors: Alan P
authors: AP
authors: Kozikowski
keywords: Nicotinic acetylcholine receptor; alkoxyisoxazole; broad screening; pharmacophore; sigma-1 receptor
references: J Med Chem. 2012 Jan 26;55(2):812-23
references: 22148173
references: Future Med Chem. 2011 Jan;3(1):79-94
references: 21428827
references: Nature. 1970 Dec 5;228(5275):917-22
references: 4921376
references: Bioorg Med Chem Lett. 2000 Jan 3;10(1):17-8
references: 10636233
references: J Pharmacol Exp Ther. 2010 Dec;335(3):762-70
references: 20864506
references: Br J Cancer. 2000 Mar;82(6):1223-32
references: 10735510
references: J Alzheimers Dis. 2011;24(3):569-86
references: 21297260
references: Science. 2009 Feb 13;323(5916):934-7
references: 19213917
references: Eur J Pharmacol. 2009 May 1;609(1-3):19-26
references: 19285059
references: Cell. 2007 Nov 2;131(3):596-610
references: 17981125
references: J Clin Psychiatry. 2008 Nov;69(11):1673-4
references: 19200426
references: Pharm Acta Helv. 2000 Mar;74(2-3):211-8
references: 10812960
references: J Med Chem. 1994 Apr 15;37(8):1214-9
references: 8164264
references: J Med Chem. 1998 Jun 18;41(13):2361-70
references: 9632369