A 61603 hydrobromide

A 61603 hydrobromide is a potent and selective agonist of α1A-adrenoceptor [1].

α1A-adrenoceptor (α1A-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.

A 61603 hydrobromide is a potent and selective α1A-adrenoceptor agonist. A-61603 was 35-fold more potent at α1A-AR than at α1B-AR or α1D-AR. In fibroblast cells transfected with α1A-AR, A-61603 significantly stimulated phosphoinositide hydrolysis [1]. A 61603 exhibited affinity for α1A-AR, α1B-AR and α1D-AR with pKi values of 8.05/7.52, 5.68 and 5.87, respectively. Also, A 61603 exhibited agonist activities for α1A-AR, α1B-AR and α1D-AR with pEC50 values of 8.24/7.66, 6.50 and 5.59, respectively [2]. In neonatal rat ventricular myocytes, A61603 significantly increased the frequency of Ca2+ transients with EC50 value of 6.9 nM in a dose-dependent way [3]. In mesenteric vascular bed isolated from mice, A61603 significantly increased perfusion pressure with 235-fold higher potency than phenylephrine, which suggested that α1A-AR plays an important role in the control of blood pressure [4].

References:
[1].  Knepper SM, Buckner SA, Brune ME, et al. A-61603, a potent alpha 1-adrenergic receptor agonist, selective for the alpha 1A receptor subtype. J Pharmacol Exp Ther, 1995, 274(1): 97-103.
[2].  Meyer MD, Altenbach RJ, Hancock AA, et al. Synthesis and in vitro characterization of N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8- tetrahydronaphthalen-1-yl]methanesulfonamide and its enantiomers: a novel selective alpha 1A receptor agonist. J Med Chem, 1996, 39(20): 4116-4119.
[3].  Luo DL, Gao J, Fan LL, et al. Receptor subtype involved in alpha 1-adrenergic receptor-mediated Ca2+ signaling in cardiomyocytes. Acta Pharmacol Sin, 2007, 28(7): 968-974.
[4].  Martínez-Salas SG1, Campos-Peralta JM, Pares-Hipolito J, et al. Alpha1A-adrenoceptors predominate in the control of blood pressure in mouse mesenteric vascular bed. Auton Autacoid Pharmacol, 2007, 27(3): 137-142.

Receptor subtype involved in alpha 1-adrenergic receptor-mediated Ca2+ signaling in cardiomyocytes.[Pubmed:17588332]

Acta Pharmacol Sin. 2007 Jul;28(7):968-74.

AIM: The enhancement of intracellular Ca2+ signaling in response to alpha 1-adrenergic receptor (alpha 1-AR) stimulation is an essential signal transduction event in the regulation of cardiac functions, such as cardiac growth, cardiac contraction, and cardiac adaptation to various situations. The present study was intended to determine the role(s) of the alpha 1-AR subtype(s) in mediating this response. METHODS: We evaluated the effects of subtype-specific agonists and antagonists of the alpha 1- AR on the intracellular Ca2+ signaling of neonatal rat ventricular myocytes using a confocal microscope. RESULTS: After being cultured for 48 h, the myocytes exhibited spontaneous local Ca2+ release, sparks, and global Ca2+ transients. The activation of the alpha 1-AR with phenylephrine, a selective agonist of the alpha 1-AR, dose-dependently increased the frequency of Ca2+ transients with an EC50 value of 2.3 micromol/L. Blocking the alpha 1A-AR subtype with 5-methylurapidil (5-Mu) inhibited the stimulatory effect of phenylephrine with an IC(50) value of 6.7 nmol/L. In contrast, blockade of the alpha 1B-AR and alpha 1D-AR subtypes with chloroethylclonidine and BMY 7378, respectively, did not affect the phenylephrine effect. Similarly, the local Ca2+ spark numbers were also increased by the activation of the alpha 1-AR, and this effect could be abolished selectively by 5-Mu. More importantly, A61603, a novel selective alpha 1A-AR agonist, mimicked the effects of phenylephrine, but with more potency (EC(50) value =6.9 nmol/L) in the potentiation of Ca2+ transients, and blockade of the alpha 1A-AR by 5-Mu caused abolishment of its effects. CONCLUSION: These results indicate that alpha 1-adrenergic stimulation of intracellular Ca2+ activity is mediated selectively by the alpha 1A-AR.

Synthesis and in vitro characterization of N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8- tetrahydronaphthalen-1-yl]methanesulfonamide and its enantiomers: a novel selective alpha 1A receptor agonist.[Pubmed:8831777]

J Med Chem. 1996 Sep 27;39(20):4116-9.

The existence of multiple subtypes of the alpha 1 adrenergic receptor has been demonstrated both pharmacologically and by molecular biological cloning techniques. The development of subtype selective antagonists has been the focus of much research within the pharmaceutical industry, and clinical evidence now exists that alpha-1A selective antagonists will have utility in the treatment of benign prostatic hyperplasia. However, highly subtype selective agonists are not known. Herein we report the synthesis and pharmacological characterization of N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8- tetrahydronaphthalen-1-yl]methanesulfonamide and its enantiomers, a highly potent full agonist with excellent selectivity for the alpha 1A receptor subtype.

A-61603, a potent alpha 1-adrenergic receptor agonist, selective for the alpha 1A receptor subtype.[Pubmed:7616455]

J Pharmacol Exp Ther. 1995 Jul;274(1):97-103.

N-[5-(4,5-dihydro-1H-imidazol-2yl)-2-hydroxy-5,6,7,8-tetrahydro naphthalen-1-yl] methanesulfonamide hydrobromide (A-61603) is a novel and potent alpha-adrenoceptor agonist. In radioligand binding assays, the compound is at least 35-fold more potent at alpha 1A/a receptors than at alpha 1b or alpha 1d sites. In fibroblast cells transfected with alpha 1a receptors, A-61603 more potently stimulates phosphoinositide hydrolysis than norepinephrine, and is antagonized by prazosin. A-61603 is less potent in cells transfected with alpha 1b or alpha 1d receptors. A-61603 is a potent agonist at alpha 1A receptors in rat vas deferens (200- to 300-fold more potent than norepinephrine or phenylephrine, respectively) and in isolated canine prostate strips (130- to 165-fold more potent than norepinephrine or phenylephrine, respectively). In contrast, A-61603 is only 40-fold more potent than phenylephrine at alpha 1B sites in rat spleen and 35-fold less potent at rat aortic, alpha 1D sites. In an in vivo dog model, A-61603 raises intraurethral prostatic tone to a greater extent than mean arterial blood pressure. A-61603 induces a pressor response in conscious rats at doses 50- to 100-fold lower than phenylephrine, and the response is not attenuated by pretreatment with CEC, whereas YM-617 causes a 100-fold shift in the response. These results indicate that A-61603 is a potent adrenergic agonist, selective for alpha 1A/a receptors, and may prove a useful probe for studies of adrenergic function and alpha 1 adrenoceptor regulation of physiological functions.