Structure activity relationships of a series of buspirone analogs at alpha-1 adrenoceptors: further evidence that rat aorta alpha-1 adrenoceptors are of the alpha-1D-subtype

DL Saussy , AS Goetz, KL Queen, HK King, MW Lutz and TJ Rimele

Department of Receptor Biochemistry, Glaxo Wellcome Research and Development, Glaxo Wellcome, Inc., Research Triangle Park, North Carolina, USA.

The activity of a series of busprione analogs at recombinant and rat thoracic aorta alpha-1 adrenoceptors was investigated. Compound affinity for recombinant alpha-1A, alpha-1B and alpha-1D adrenoceptors from human and animal sources was determined by radioligand binding assays using membranes prepared from rat-1 fibroblasts expressing recombinant receptors with ( +/- )-[125l]iodo-4-hydroxyphenyl)-ethyl- aminomethyl-tetralone as the radioligand. Compound affinity and functional activity at rat aortic alpha-1 adrenoceptors were determined using endothelium denuded rings contracted with phenylephrine. BMY 7378 8-(2-[4-(2-methoxyphenyl)-1-piperazinyl]-ehtyl)-8-azaspiro [4,5]decane- 7,9-dione dihydrochloride and MDL 73005EF 8-[2-(1,4-benzodioxan-2- ylmethylamino) ethyl]-8-azaspiro[4,5]decane-7,9-dione hydrochloride were found to have significant selectivity for the alpha-1D-subtype and were high affinity antagonists of the alpha-1 adrenoceptors in the rat aorta. Leverage plot analysis of affinities of the buspirone analogs and a series of structurally diverse alpha-1 antagonists for recombinant alpha-1 adrenoceptors and rat aorta alpha-1 adrenoceptors demonstrate that the alpha-1 adrenoceptors in the rat aorta are predominantly of the alpha-1D subtype.

Volume 278, Issue 1, pp. 136-144, 07/01/1996
Copyright © 1996 by American Society for Pharmacology and Experimental Therapeutics

This article has been cited by other articles:

				K. L. Hillman, V. A. Doze, and J. E. Porter {alpha}1A-Adrenergic Receptors Are Functionally Expressed by a Subpopulation of Cornu Ammonis 1 Interneurons in Rat Hippocampus J. Pharmacol. Exp. Ther., June 1, 2007; 321(3): 1062 - 1068. [Abstract] [Full Text] [PDF]

				D. Marti, R. Miquel, K. Ziani, R. Gisbert, M. D. Ivorra, E. Anselmi, L. Moreno, V. Villagrasa, D. Barettino, and P. D'Ocon Correlation between mRNA levels and functional role of {alpha}1-adrenoceptor subtypes in arteries: evidence of {alpha}1L as a functional isoform of the {alpha}1A-adrenoceptor Am J Physiol Heart Circ Physiol, November 1, 2005; 289(5): H1923 - H1932. [Abstract] [Full Text] [PDF]

				C. S. Bockman, M. R. Bruchas, W. Zeng, K. A. O'Connell, P. W. Abel, M. A. Scofield, and F. J. Dowd Submandibular Gland Acinar Cells Express Multiple {alpha}1-Adrenoceptor Subtypes J. Pharmacol. Exp. Ther., October 1, 2004; 311(1): 364 - 372. [Abstract] [Full Text] [PDF]

				C. Hague, P. J. Gonzalez-Cabrera, W. B. Jeffries, and P. W. Abel Relationship between alpha 1-Adrenergic Receptor-Induced Contraction and Extracellular Signal-Regulated Kinase Activation in the Bovine Inferior Alveolar Artery J. Pharmacol. Exp. Ther., October 1, 2002; 303(1): 403 - 411. [Abstract] [Full Text] [PDF]

				H. Zhang, C. S. Facemire, A. J. Banes, and J. E. Faber Different alpha -adrenoceptors mediate migration of vascular smooth muscle cells and adventitial fibroblasts in vitro Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2364 - H2370. [Abstract] [Full Text] [PDF]

				D. B.C. Queiroz, F. R. Mendes, C. S. Porto, and M. C. W. Avellar {alpha}1-Adrenoceptor Subtypes in Rat Epididymis and the Effects of Sexual Maturation Biol Reprod, February 1, 2002; 66(2): 508 - 515. [Abstract] [Full Text] [PDF]

				M. T. Piascik and D. M. Perez alpha 1-Adrenergic Receptors: New Insights and Directions J. Pharmacol. Exp. Ther., August 1, 2001; 298(2): 403 - 410. [Abstract] [Full Text] [PDF]

				S. Guimaraes and D. Moura Vascular Adrenoceptors: An Update Pharmacol. Rev., June 1, 2001; 53(2): 319 - 356. [Abstract] [Full Text] [PDF]

				R. Gisbert, M. A. Noguera, M. D. Ivorra, and P. D'Ocon Functional Evidence of a Constitutively Active Population of alpha 1D-Adrenoceptors in Rat Aorta J. Pharmacol. Exp. Ther., November 1, 2000; 295(2): 810 - 817. [Abstract] [Full Text]

				E. E. Daniel, R. D. Brown, Y. F. Wang, A. M. Low, H. Lu-Chao, and C.-Y. Kwan alpha -Adrenoceptors in Canine Mesenteric Artery Are Predominantly 1A Subtype: Pharmacological and Immunochemical Evidence J. Pharmacol. Exp. Ther., November 1, 1999; 291(2): 671 - 679. [Abstract] [Full Text]

				H. Yokoyama, M. Yasutake, and M. Avkiran {alpha}1-Adrenergic Stimulation of Sarcolemmal Na+-H+ Exchanger Activity in Rat Ventricular Myocytes : Evidence for Selective Mediation by the {alpha}1A-Adrenoceptor Subtype Circ. Res., June 1, 1998; 82(10): 1078 - 1085. [Abstract] [Full Text] [PDF]

				A. M. Low, H. Lu-Chao, Y. F. Wang, R. D. Brown, C. Y. Kwan, and E. E. Daniel Pharmacological and Immunocytochemical Characterization of Subtypes of Alpha-1 Adrenoceptors in Dog Aorta J. Pharmacol. Exp. Ther., May 1, 1998; 285(2): 894 - 901. [Abstract] [Full Text]

				A. Leonardi, J. P. Hieble, L. Guarneri, D. P. Naselsky, E. Poggesi, G. Sironi, A. C. Sulpizio, and R. Testa J. Pharmacol. Exp. Ther., June 1, 1997; 281(3): 1272 - 1283. [Abstract] [Full Text]

				R. Testa, L. Guarneri, P. Angelico, E. Poggesi, C. Taddei, G. Sironi, D. Colombo, A. C. Sulpizio, D. P. Naselsky, J. P. Hieble, et al. J. Pharmacol. Exp. Ther., June 1, 1997; 281(3): 1284 - 1293. [Abstract] [Full Text]

				H. Zhang, C. S. Facemire, A. J. Banes, and J. E. Faber Different alpha -adrenoceptors mediate migration of vascular smooth muscle cells and adventitial fibroblasts in vitro Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2364 - H2370. [Abstract] [Full Text] [PDF]

				H. Zhang and J. E. Faber Trophic Effect of Norepinephrine on Arterial Intima-Media and Adventitia Is Augmented by Injury and Mediated by Different {alpha}1-Adrenoceptor Subtypes Circ. Res., October 26, 2001; 89(9): 815 - 822. [Abstract] [Full Text] [PDF]