TY - JOUR T1 - Benzylidene Analogs of Anabaseine Display Partial Agonist and Antagonist Properties at the Mouse 5-Hydroxytryptamine<sub>3A</sub>Receptor JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 1112 LP - 1119 VL - 299 IS - 3 AU - Tina K. Machu AU - Margaret E. Hamilton AU - Tonia F. Frye AU - Christopher L. Shanklin AU - Michael C. Harris AU - Hongwei Sun AU - Thomas E. Tenner, Jr. AU - Ferenc S. Soti AU - William R. Kem Y1 - 2001/12/01 UR - http://jpet.aspetjournals.org/content/299/3/1112.abstract N2 - The nicotinic receptor drug candidate, 3-(2,4-dimethoxybenzylidene)-anabaseine (also known as GTS-21; DMXBA), its hydroxy metabolites, and some related analogs were evaluated with the two-electrode voltage-clamp technique in mouse 5-hydroxytryptamine (5-HT)3A receptors expressed in Xenopusoocytes. Although DMXBA lacked partial agonist activity, its hydroxy-benzylidene metabolites and related analogs were partial agonists, displaying the following rank order of potency (EC50) and apparent efficacy: 5-HT, 0.9 ± 0.06 μM (100% efficacy) &gt; 3-(2-hydroxy,4-methoxybenzylidene)-anabaseine (2-OH-MBA), 2.0 ± 0.3 μM (63% efficacy) &gt; 3-(2,4-dihydroxybenzylidene)-anabaseine, 2.6 ± 0.3 μM (63% efficacy) &gt; 3-(2-methoxy,4-hydroxybenzylidene)-anabaseine, 17.2 ± 1.0 μM (30% efficacy). To examine the influence of a benzylidene ring hydroxy substituent, the agonist actions of the three possible monohydroxy isomers were examined. The rank order of potency, based on EC50 determinations, and apparent efficacy was: 3-(2-hydroxybenzylidene)-anabaseine, 20.3 ± 2.6 μM (63% efficacy) &gt; 3-(4-hydroxybenzylidene)-anabaseine, 32.3 ± 5.9 μM (14% efficacy) &gt; 3-(3-hydroxybenzylidene)-anabaseine (3-OH-BA) (no agonist activity). Both DMXBA and 3-OH-BA antagonized 5-HT-mediated currents, with IC50 values of 15.7 ± 0.9 and 27.5 ± 4.7 μM, respectively. DMXBA demonstrated both competitive and noncompetitive forms of antagonism over the range of concentrations tested. These results suggest that a hydroxy substituent at the 2′ position of the benzene ring is necessary and sufficient for partial agonist activity; substitution at the 4′ position with a hydroxy or methoxy group further enhances agonist potency. Because 2-OH-MBA is a primary metabolite of DMXBA, it may contribute to the physiological, biochemical, and behavioral effects of the parent compound when administered in vivo. The American Society for Pharmacology and Experimental Therapeutics ER -