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NEUROPHARMACOLOGY

N-Terminal Domains in Mouse and Human 5-Hydroxytryptamine_3A Receptors Confer Partial Agonist and Antagonist Properties to Benzylidene Analogs of Anabaseine

Department of Pharmacology and Neuroscience (R.Z., N.A.W., T.K.M.) and Department of Anesthesiology (T.K.M.), Texas Tech University Health Sciences Center, Lubbock, Texas; and Department of Pharmacology and Therapeutics (F.S.S., W.R.K.), University of Florida Health Sciences Center, Gainesville, Florida

The present study tested the hypothesis that mouse and human 5-hydroxytryptamine_3A (5-HT_3A) receptors may be differentially modulated by benzylidene analogs of anabaseine (BA) and that these analogs may be useful in assessing residues involved in receptor gating. Mouse and human wild-type and mouse and human chimeric 5-HT_3A receptors expressed in Xenopus oocytes were evaluated with the two-electrode voltage clamp technique. Our previous studies demonstrated that 3-(2,4-dimethoxybenzylidene)-anabaseine (DMXBA) is an antagonist at the mouse wild-type 5-HT_3A receptor, but that its metabolites 3-(2-hydroxy, 4-methoxybenzylidene)-anabaseine (2-OHMBA), 3-(2-methoxy, 4-hydroxybenzylidene)-anabaseine (4-OHMBA), and 3-(2,4-dihydroxybenzylidene)-anabaseine (2,4-DiOHBA) are partial agonists (J Pharmacol Exp Ther, 299: 1112–1117, 2001). In the human wild-type (HWT) 5-HT_3A receptor, none of the BA compounds possessed partial agonist activity. BA compounds antagonized 1.5 µM 5-HT-mediated (EC₅₀) responses in the HWT 5-HT_3A receptor with a rank order of potency (IC₅₀ in µM) of 2-OHMBA (1.5 ± 0.1) > DMXBA (3.1 ± 0.2) > 4-OHMBA (7.4 ± 0.5) > 2,4-DiOHBA (12.8 ± 0.7). In mouse receptor chimeras containing N-terminal human receptor orthologs, 2-OHMBA inhibited 5-HT-mediated (EC₅₀) currents with IC₅₀ values of 2.0 ± 0.08 and 3.0 ± 0.13 µM, respectively. In human receptor chimeras containing N-terminal mouse receptor orthologs, 2-OHMBA displayed partial agonist activities with EC₅₀ values of 1.3 ± 0.15 and 5.0 ± 0.4 µM; efficacies were 43 and 57%, respectively. Thus, amino acids present in the distal one-third of the N terminus of mouse and human 5-HT_3A receptors are necessary and sufficient to confer partial agonist or antagonist properties of 2-OHMBA.

Address correspondence to: Dr. Tina K. Machu, Dept. of Pharmacology and Neuroscience, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., Ft. Worth, TX 76107-2699. E-mail: tmachu{at}hsc.unt.edu

This article has been cited by other articles:

				A. N. de Oliveira-Pierce, R. Zhang, and T. K. Machu Colchicine: A Novel Positive Allosteric Modulator of the Human 5-Hydroxytryptamine3A Receptor J. Pharmacol. Exp. Ther., May 1, 2009; 329(2): 838 - 847. [Abstract] [Full Text] [PDF]