title: Buspirone functionally discriminates tissues endowed with alpha1-adrenoceptor subtypes A, B, D and L.
abstract: The affinity for functional alpha1-adrenoceptor subtypes of buspirone in comparison with its close structural analogs and selective alpha1D-adrenoceptor antagonists, BMY 7378 (8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]dec ane-7,9-dione) and MDL 73005EF (8-[2-(1,4-benzodioxan-2-ylmethylamino)ethyl]-8-azaspiro+ ++[4.5]decane-7,9-dione), was determined, namely at subtype A in rat vas deferens and perfused kidney, at subtype B in guinea-pig and mouse spleen, at subtype L in rabbit spleen, and at subtype D in rat aorta and pulmonary artery against noradrenaline-evoked contractions. BMY 7378 and MDL 73005EF were confirmed as 30- and 20-fold selective antagonists, respectively, for alpha1D- over both alpha1A- and alpha1B-adrenoceptors. Buspirone was a weak antagonist without intrinsic activity at alpha1A-adrenoceptors in rat vas deferens (pA2 = 6.12), at alpha1B-adrenoceptors in guinea-pig and mouse spleen (pA2 = 5.54 and 5.59) and at alpha1L-adrenoceptors in rabbit spleen (pA2 = 4.99), but caused partial vasoconstriction in rat kidney that was attenuable by the subtype D-selective adrenoceptor antagonist BMY 7378, but hardly by the subtype A-selective adrenoceptor antagonist B8805-033 ((+/-)-1,3,5-trimethyl-6-[[3-[4-((2,3-dihydro-2-hydroxymethyl)-1,4-be nzodioxin-5-yl)-1-piperazinyl]propyl]amino]-2,4(1H,3H)-pyrimidinedion e), confirming the additional presence of alpha1D-adrenoceptors mediating rat renal vasoconstriction. Buspirone behaved as a partial agonist at alpha1D-adrenoceptors in rat aorta (pD2 = 6.77, intrinsic activity (i.a.)= 0.40) and pulmonary artery (pD2 = 7.16, i.a. = 0.59). With buspirone as agonist in these tissues, the pA2 values of subtype-discriminating antagonists were consistent with their alpha1D-adrenoceptor affinity determined in rat aorta against noradrenaline and with published binding data on cloned alpha1d-adrenoceptors. The results provide pharmacological evidence that (1) in functional preparations for the A subtype, like rat vas deferens and perfused kidney, for the B subtype, like guinea-pig and mouse spleen, and for the L subtype, like rabbit spleen, buspirone is a weak antagonist without intrinsic activity, but (2) behaves as a partial agonist in rat aorta and pulmonary artery as models for the D subtype and (3) detects an additional vasoconstrictor alpha1D-adrenoceptor in rat kidney. Buspirone, like its close analogs BMY 7378 and MDL 73005EF, thus might also be a useful tool for functionally discriminating alpha1D- from alpha1A-, alpha1B- and alpha1L-adrenoceptors in various tissues.
authors.affiliation: Department of Pharmacology, Konstanz, Germany. manfrid.eltze@byk.gulden.de
authors.forename: M
authors.initials: M
authors.lastname: Eltze
authors.forename: H
authors.initials: H
authors.lastname: König
authors.forename: B
authors.initials: B
authors.lastname: Ullrich
authors.forename: T
authors.initials: T
authors.lastname: Grebe
mesh_terms: D000322:Adrenergic Agonists / Q000494:pharmacology*; D018674:Adrenergic Antagonists / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic; D002065:Buspirone / Q000494:pharmacology*; D004147:Dioxins / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D016014:Linear Models; D008297:Male; D051379:Mice; D010879:Piperazines / Q000494:pharmacology; D011651:Pulmonary Artery; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D011941:Receptors, Adrenergic / Q000187:drug effects / Q000378:metabolism*; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D013141:Spiro Compounds / Q000494:pharmacology; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D014649:Vas Deferens / Q000187:drug effects / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: C547714:Adra1a protein, mouse; C547715:Adra1a protein, rat; C547717:Adra1b protein, mouse; C547718:Adra1b protein, rat; C547720:Adra1d protein, mouse; C547721:Adra1d protein, rat; D000322:Adrenergic Agonists; D018674:Adrenergic Antagonists; D004147:Dioxins; D010879:Piperazines; D011941:Receptors, Adrenergic; D018340:Receptors, Adrenergic, alpha-1; D013141:Spiro Compounds; C063249:binospirone mesylate; C053428:BMY 7378; D002065:Buspirone