α1-Adrenoceptor Characteristics and Modulators

Alpha 1 Adrenoceptor Activation

α₁-Adrenoceptors are widely distributed, and are activated either by norepinephrine released from sympathetic nerve terminals or by epinephrine released from the adrenal medulla. Receptor activation mediates a variety of functions, including contraction of smooth muscle, cardiac stimulation, cellular proliferation/apoptosis and activation of hepatic gluconeogenesis and glycogenolysis. α₁-Adrenoceptors are also widely distributed within the CNS, where their activation generally results in depolarization and increased neuronal firing rate. Most of the peripheral actions of α₁-adrenoceptors are mediated through phosphatidylinositol turnover, while there is evidence for activation of adenylyl cyclase within the CNS.

Subtypes

Three distinct α₁-adrenoceptor proteins have been cloned; after some confusion in nomenclature, it has now been established that these three recombinant α₁-adrenoceptors, designated as α_1a, α_1b and α_1d correspond to the pharmacologically defined α_1a, α_1b and α_1d adrenoceptors in native tissues. Multiple slice variants of the α_1a adrenoceptor have been identified; however, they appear to have identical pharmacological characteristics. The α₁-adrenoceptor mediating contraction of several vascular and urogenital tissues has distinct pharmacology from the other 3 subtypes, and has been designated as the α_1I adrenoceptor. This receptor has not been cloned; it now appears that the α_1I adrenoceptor represents a discrete affinity state of the α_1a adrenoceptor.

Selective Expression

The subcellular location of expressed recombinant α₁-adrenoceptors may be subtype dependent. Chloroethylclonidine, commonly used as a selective α_1b antagonist for receptor subclassification, may be able to alkylate all α₁-adrenoceptors, with its apparent selectivity for α_1b versus α_1a adrenoceptors, at least in cells expressing recombinant receptors, due to accessibility only to the α_1b receptor. Evidence shows that it may be possible to design peptides which can selectively antagonize α₁-adrenoceptor subtypes.

Mediated Response

In most cases, the particular subtype involved in an α₁-adrenoceptor mediated response has not yet been defined. This is due in part to the lack of subtype selective antagonists suitable for in vivo evaluation. Depending on the species and/or vascular bed, each α₁-adrenoceptor subtype can contribute to vascular contraction. For example, contraction of the rat caudal artery is mediated by the α_1a adreceptor, canine aorta by the α_1b and rat aorta by the α_1d adrenoceptor. The response to α₁-adrenoceptor stimulation in many canine and human vessels has α_1I pharmacology. Knockout of either α_1a, α_1b or α_1d adrenoceptor significantly attenuates the pressor response to α₁-adrenoceptor activation in the mouse. Contraction of prostatic and urethral smooth muscle appears to be mediated by the α_1I adrenoceptor. α₁-Adrenoceptor antagonists having selective affinity for α_1a and α_1I adrenoceptors, as well as antagonists having affinity for both α_1a and α_1d adrenoceptors, have been evaluated clinically for the treatment of benign prostatic hyperplasia. However, it appears that these drugs are not superior to the non-subtype selective α₁-adrenoceptor antagonists, which have been proven to be effective for this indication.

Accepted Alpha 1 Adrenoreceptor Modulators

The table below contains accepted modulators and additional information. Compare these modulators as well as several similar products (A0232, SML0460) in the "All Products" section that follows.

Abbreviations

A-61603: N-[5-(4,5-Dihydro-1H-imidazol-2yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]methanesulfonamide hydrobromide
BMY 7378: 8-[2-[4-(2-Methoxyphenyl)-1-piperazinyl]ethyl]-8-azasprio[4.5]decane-7,9-dione
HEAT: 2-(β-4-Hydroxyphenyl)ethylaminomethyltetralone
L-762,459: (±)-1-(3-{[5-Carbamoyl-2-{2-[(4-hydroxy-3-iodobenzimidoyl)-amino]-ethoxy-methyl}-6-methyl-4-(4-nitrophenyl)-1,4-dihydropyridine-4-carboxylic acid methyl ester
L-765,314: 4-Amino-2-[4-[1-(benzyloxycarbonyl)-2(S)-[[(1,1-dimethylethyl)amino]carbonyl]-piperazinyl]-6,7-dimethoxyquinazoline
RS-17053: (N-[2-(2-Cyclopropylmethoxyphenoxy)ethyl]-5-chloro-α,α-dimethyl-1H-indole-3-ethanamine
SKF-89748: 1,2,3,4-Tetrahydro-8-methoxy-5-(methylthio)-2-naphthalenamine