title: Benzylidene analogs of anabaseine display partial agonist and antagonist properties at the mouse 5-hydroxytryptamine(3A) receptor.
abstract: 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 Xenopus oocytes. Although DMXBA lacked partial agonist activity, its hydroxy-benzylidene metabolites and related analogs were partial agonists, displaying the following rank order of potency (EC(50)) and apparent efficacy: 5-HT, 0.9 +/- 0.06 microM (100% efficacy) > 3-(2-hydroxy,4-methoxybenzylidene)-anabaseine (2-OH-MBA), 2.0 +/- 0.3 microM (63% efficacy) > 3-(2,4-dihydroxybenzylidene)-anabaseine, 2.6 +/- 0.3 microM (63% efficacy) > 3-(2-methoxy,4-hydroxybenzylidene)-anabaseine, 17.2 +/- 1.0 microM (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 EC(50) determinations, and apparent efficacy was: 3-(2-hydroxybenzylidene)-anabaseine, 20.3 +/- 2.6 microM (63% efficacy) > 3-(4-hydroxybenzylidene)-anabaseine, 32.3 +/- 5.9 microM (14% efficacy) > 3-(3-hydroxybenzylidene)-anabaseine (3-OH-BA) (no agonist activity). Both DMXBA and 3-OH-BA antagonized 5-HT-mediated currents, with IC(50) values of 15.7 +/- 0.9 and 27.5 +/- 4.7 microM, 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.
authors.affiliation: Department of Pharmacology, Texas Tech University Health Sciences Center, Lubbock, Texas 79430, USA. tina.machu@ttmc.ttuhsc.edu
authors.forename: T K
authors.initials: TK
authors.lastname: Machu
authors.forename: M E
authors.initials: ME
authors.lastname: Hamilton
authors.forename: T F
authors.initials: TF
authors.lastname: Frye
authors.forename: C L
authors.initials: CL
authors.lastname: Shanklin
authors.forename: M C
authors.initials: MC
authors.lastname: Harris
authors.forename: H
authors.initials: H
authors.lastname: Sun
authors.forename: T E
authors.initials: TE
authors.lastname: Tenner
authors.forename: F S
authors.initials: FS
authors.lastname: Soti
authors.forename: W R
authors.initials: WR
authors.lastname: Kem
mesh_terms: D000691:Anabasine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D001597:Benzylidene Compounds / Q000494:pharmacology*; D001665:Binding Sites; D004594:Electrophysiology; D018722:Nicotinic Agonists / Q000494:pharmacology; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism*; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D014982:Xenopus laevis
chemical_list: D001597:Benzylidene Compounds; D018722:Nicotinic Agonists; D011725:Pyridines; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C088936:3-(2,4-dimethoxybenzylidene)anabaseine; C091713:anabaseine; D000691:Anabasine