Failure of AH11110A to functionally discriminate between alpha(1)-adrenoceptor subtypes A, B and D or between alpha(1)- and alpha(2)-adrenoceptors

TThe potency of the putatively alpha (1B)-adrenoceptor selective drug, 1-[b iphenyl-2-yloxy]-4-imino-4-piperidin-1-yl-butan-2ol (AH11110A), to antagoni ze contraction upon stimulation of alpha (1A)-adrenoceptors in rat vas defe rens and rat perfused kidney, alpha (1B)-adrenoceptors in guinea-pig spleen , mouse spleen and rabbit aorta, and alpha (1D)-adrenoceptors in rat aorta and pulmonary artery was evaluated and compared to that of a number of subt ype-discriminating antagonists. N-[3-[4-(2-Methoxyphenyl)-1-piperaziny]prop yl]-3 -methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxamide (Rec 15/2739) an d (+/-)-1,3,5-trimethyl-6-[[3-[4-((2,3-dihydro-2-hydroxymethyl)-1,4-benzodi oxin-5- yl)-l-piperazinyl]propyl]amino]-2,4(1H,3H)-pyrimidinedione (B8805-0 33) were confirmed as selective for alpha (1A)-adrenoceptors, 8-[2-[4(2-met hoxyphenyl)- l-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione (BMY 7378 ), 8-[2-(1,4-benzodioxan-2-ylmethylamino)ethyl]-8 azaspiro[4.5]decane-7,9-d ione (MDL 73005EF), and cystazosin were found to be selective for alpha (1D )-adrenoceptors, whereas spiperone was weakly selective for alpha (1B)-over alpha (1A)-adrenoceptors. However, from the functional affinity profile ob tained for AH11110A at alpha (1A)-adrenoceptors (pA(2) = 6.41 in rat vas de ferens), alpha (1B)-adrenoceptors (pA(2) = 5.40-6.54) and alpha (1D)-adreno ceptors (pA(2) = 5.47-5.48), the affinity and presumed selectivity previous ly obtained for AH11110A in radioligand binding studies at native alpha (1B )- and cloned alpha (1b)-adrenoceptors (pK(i) = 7.10-7.73) could not be con firmed. Additionally, AH11110A enhanced the general contractility of rat va s deferens, produced a bell-shaped dose-response curve of vasodilation in p erfused rat kidney, and its antagonism in most other tissues was not simply competitive. The affinity of AH11110A far prejunctional alpha (2)-adrenoce ptors in rabbit vas deferens (pA(2) = 5.44) was not much lower than that di splayed for alpha (1)-adrenoceptor subtypes, revealing that AH11110A, besid es alpha (1)-adrenoceptors, also interacts with alpha (2)-adrenoceptors, an d thus may be unsuitable for alpha -adrenoceptor subtype characterization, at least in smooth muscle containing functional studies. (C) 2001 Elsevier Science B.V. All rights reserved.