1.In vivo characterization and dynamic receptor occupancy imaging of TPA023B, an alpha 2/alpha 3/alpha 5 subtype selective gamma-aminobutyric acid-a partial agonist.
Van Laere K1, Bormans G, Sanabria-Bohórquez SM, de Groot T, Dupont P, De Lepeleire I, de Hoon J, Mortelmans L, Hargreaves RJ, Atack JR, Burns HD. Biol Psychiatry. 2008 Jul 15;64(2):153-61. doi: 10.1016/j.biopsych.2008.01.021. Epub 2008 Mar 14.
BACKGROUND: A novel, high-affinity (.7-2.0 nmol) compound that selectively activates the alpha2, alpha 3, and alpha 5 (but not alpha1) gamma-aminobutyric acid-A (GABA(A)) receptor subtypes, TPA023B (2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl) imidazo[1,2-b][1,2,4]triazin-7-yl][1,1'-biphenyl]-2-carbonitrile) was pharmacologically characterized and studied by means of positron emission tomography (PET) to determine dynamic occupancies of the benzodiazepine binding site of human brain GABA(A) receptors after a single oral dose.
2.GW427353 (solabegron), a novel, selective beta3-adrenergic receptor agonist, evokes bladder relaxation and increases micturition reflex threshold in the dog.
Hicks A1, McCafferty GP, Riedel E, Aiyar N, Pullen M, Evans C, Luce TD, Coatney RW, Rivera GC, Westfall TD, Hieble JP. J Pharmacol Exp Ther. 2007 Oct;323(1):202-9. Epub 2007 Jul 12.
Functional studies have demonstrated that adrenoceptor agonist-evoked relaxation is mediated primarily by beta3-adrenergic receptors (ARs) in human bladder. Thus, the use of selective beta3-AR agonists in the pharmacological treatment of overactive bladder is being explored. The present studies investigated the effects of a novel selective beta3-AR agonist, (R)-3'-[[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]amino]-[1,1'-biphenyl]-3-carboxylic acid (GW427353; solabegron) on bladder function in the dog using in vitro and in vivo techniques. GW427353 stimulated cAMP accumulation in Chinese hamster ovary cells expressing the human beta3-AR, with an EC50 value of 22 +/- 6 nM and an intrinsic activity 90% of isoproterenol. At concentrations of 10,000 nM, GW427353 produced a minimal response in cells expressing either beta1-ARs or beta2-ARs (maximum response <10% of that to isoproterenol). In dog isolated bladder strips, GW427353 evoked relaxation that was attenuated by the nonselective beta-AR antagonist bupranolol and 1-(2-ethylphenoxy)-3-[[(1S)-1,2,3,4-tetrahydro-1-naphthalenyl]amino]-(2S)-2-propanol (SR59230A) (reported to have beta3-AR antagonist activity).