title: Sigma1 and sigma2 receptor binding affinity and selectivity of SA4503 and fluoroethyl SA4503.
abstract: SA4503, a potent sigma(1) receptor agonist, is reported as having 103-fold higher affinity for sigma(1) (IC(50) = 17.4 nM) than sigma(2) (IC(50) = 1,784 nM) sites in guinea pig brain membranes. Modest structural changes appear to have major effects on sigma(1)/sigma(2) selectivity. The fluoroethyl analog, FE-SA4503, is described as having high primary affinity for sigma(2) sites (IC(50) = 2.11 nM) and a weaker interaction with sigma(1) sites (IC(50) = 6.48 nM). SA4503 and FE-SA4503 have been radiolabeled for PET studies, and both bind selectively to sigma(1) receptors in animal and human brain in vivo. We prepared SA4503 and FE-SA4503 as reference compounds for radioligand development efforts. In our hands, SA4503 is 14-fold selective for sigma(1) (K(i) = 4.6 nM) over sigma(2) (K(i) = 63.1 nM) sites in guinea pig brain homogenates. Further, FE-SA4503 exhibits the same 14-fold selectivity for sigma(1) (K(i) = 8.0 nM) over sigma(2) (K(i) = 113.2 nM) receptors. The main differences from previously reported values stem from sigma(2) affinity determinations. This protocol, displacement of [(3)H]DTG binding to sigma(2) sites using (+)-pentazocine (200 nM) to mask sigma(1) sites, was validated by the proper rank order of sigma(2) inhibitory potencies shown by a panel of additional ligands: ifenprodil > haloperidol > DTG >> (+)-pentazocine. Robust Pearson correlation (r = 1.0, P = 0.002; slope = 0.97) was observed for our pK(i) values against those from a prior study by others. The findings have bearing on structure-activity relationships for this active series, and on conclusions that might be drawn from experiments relying upon defined sigma(1)/sigma(2) binding selectivity.
authors.affiliation: Department of Radiology, University of Missouri-Columbia, 65211, USA. leverj@health.missouri.edu
authors.forename: John R
authors.initials: JR
authors.lastname: Lever
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Gustafson
authors.forename: Rong
authors.initials: R
authors.lastname: Xu
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Allmon
authors.forename: Susan Z
authors.initials: SZ
authors.lastname: Lever
mesh_terms: D000818:Animals; D001345:Autoradiography / Q000379:methods; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics*; D006146:Guanidines / Q000493:pharmacokinetics; D006168:Guinea Pigs; D006220:Haloperidol / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008024:Ligands; D008297:Male; D009292:Narcotic Antagonists / Q000494:pharmacology; D010423:Pentazocine / Q000494:pharmacology; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects*; D011869:Radioligand Assay / Q000379:methods; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D017480:Receptors, sigma / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D018492:Dopamine Antagonists; C451922:FE-SA4503; D005462:Fluorine Radioisotopes; D006146:Guanidines; D008024:Ligands; D009292:Narcotic Antagonists; D010879:Piperazines; D019275:Radiopharmaceuticals; D017480:Receptors, sigma; C101789:SA 4503; D006220:Haloperidol; C050232:1,3-ditolylguanidine; D010423:Pentazocine