AH 11110 hydrochloride

AH 11110 hydrochloride is a selective antagonist of α1B-adrenoceptor [1].

α1B-adrenoceptor (α1B-AR) belongs to α1- adrenergic receptors, which include three subtypes α1A, α1B and α1D and play an important role in regulating cell growth and proliferation.

AH 11110 hydrochloride is a selective α1B-AR antagonist. AH11110A inhibited cloned α1B-AR with Ki value of 79.4 nM and exhibited 32- and 26-fold selectivity over α1A- and α1D-ARs, respectively [1]. In rat vas deferens and rat perfused kidney, AH11110A exhibited affinities for α1A-AR, α1B-AR and α1D-AR with pA2 values of 6.41, 5.40-6.54 and 5.47-5.48, respectively. Also, AH11110A displayed affinity for α2-adrenoceptor in rabbit vas deferens with pA2 value of 5.44. In ligand binding studies, AH11110A exhibited affinities for native and cloned α1B-AR with pKi of 7.10-7.73. AH11110A increased contraction of rat vas deferens [2]. In isolated spleen strips from guinea-pig, AH11110A competitively antagonized tissue contraction induced by noradrenaline in a concentration-dependent way [2].

References:
[1].  Erami C, Zhang H, Ho JG, et al. Alpha(1)-adrenoceptor stimulation directly induces growth of vascular wall in vivo. Am J Physiol Heart Circ Physiol, 2002, 283(4): H1577-1587.
[2].  Eltze M, König H, Ullrich B, et al. Failure of AH11110A to functionally discriminate between alpha(1)-adrenoceptor subtypes A, B and D or between alpha(1)- and alpha(2)-adrenoceptors. Eur J Pharmacol, 2001, 415(2-3): 265-276.

Competitive and allosteric interactions of 6-chloro-5,10-dihydro-5-[(1-methyl-4-piperidinyl)acetyl]-11H-di benzo[b,e][1, 4]diazepine-11-one hydrochloride (UH-AH 37) at muscarinic receptors, via distinct epitopes.[Pubmed:9890566]

Biochem Pharmacol. 1999 Jan 15;57(2):181-6.

6-Chloro-5,10-dihydro-5-[( 1-methyl-4-piperidinyl)acetyl]-11H-dibenzo[b,e][1,4]diazepine-11one++ + hydrochloride (UH-AH 37) is an analog of pirenzepine that has previously been reported to interact with classical muscarinic antagonists in a competitive manner, yet its binding has also been found to be sensitive to the same epitope as is that of the allosteric ligand gallamine. The present study was carried out with wild-type and chimeric muscarinic receptors to determine whether UH-AH 37 might also have an allosteric mode of action. In assays that detect only allosteric interactions, UH-AH 37 slowed the rate of dissociation of [3H]N-methylscopolamine (NMS) from all five muscarinic receptor subtypes, with the highest apparent affinity at m2. By contrast, studies carried out under equilibrium conditions have found UH-AH 37 to have the lowest affinity for the m2 subtype. Studies with m2/m5 chimeric receptors found the allosteric potency of UH-AH 37 to be sensitive to an epitope in the seventh transmembrane domain (TM). Again, this contrasts with equilibrium studies, wherein an epitope in the sixth TM has been implicated. Simultaneous analysis of the interactions between UH-AH 37 and [3H]NMS at the m2 receptor under equilibrium and non-equilibrium conditions found that a simple allosteric model could not accommodate both sets of data. On the other hand, the model did accommodate such data for gallamine; gallamine also displays concordance in order-of-potency and epitope sensitivity between equilibrium and non-equilibrium assays. Based on these results, we conclude that UH-AH 37 interacts at the classical muscarinic binding site with high affinity and at a second (allosteric) site with lower affinity.

Failure of AH11110A to functionally discriminate between alpha(1)-adrenoceptor subtypes A, B and D or between alpha(1)- and alpha(2)-adrenoceptors.[Pubmed:11275009]

Eur J Pharmacol. 2001 Mar;415(2-3):265-76.

The potency of the putatively alpha(1B)-adrenoceptor selective drug, 1-[biphenyl-2-yloxy]-4-imino-4-piperidin-1-yl-butan-2-ol (AH11110A), to antagonize contraction upon stimulation of alpha(1A)-adrenoceptors in rat vas deferens 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 subtype-discriminating antagonists. N-[3-[4-(2-Methoxyphenyl)-1-piperazinyl]propyl]-3-methyl-4-oxo-2-phenyl-4H-1-benz opyran-8-carboxamide (Rec 15/2739) and (+/-)-1,3,5-trimethyl-6-[[3-[4-((2,3-dihydro-2-hydroxymethyl)-1,4-benzodioxin-5-y l)-1-piperazinyl]propyl]amino]-2,4(1H,3H)-pyrimidinedione (B8805-033) were confirmed as selective for alpha(1A)-adrenoceptors, 8-[2-[4-(2-methoxyphenyl)-1-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-dione (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 obtained for AH11110A at alpha(1A)-adrenoceptors (pA(2)=6.41 in rat vas deferens), alpha(1B)-adrenoceptors (pA(2)=5.40-6.54) and alpha(1D)-adrenoceptors (pA(2)=5.47-5.48), the affinity and presumed selectivity previously 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 confirmed. Additionally, AH11110A enhanced the general contractility of rat vas deferens, produced a bell-shaped dose-response curve of vasodilation in perfused rat kidney, and its antagonism in most other tissues was not simply competitive. The affinity of AH11110A for prejunctional alpha(2)-adrenoceptors in rabbit vas deferens (pA(2)=5.44) was not much lower than that displayed for alpha(1)-adrenoceptor subtypes, revealing that AH11110A, besides alpha(1)-adrenoceptors, also interacts with alpha(2)-adrenoceptors, and thus may be unsuitable for alpha-adrenoceptor subtype characterization, at least in smooth muscle containing functional studies.