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.

Name	α1A	α1B	α1D
Alternate Name	α1a, α1c	α1b	α1d, α1a/d
Structural Information	466 aa (human)	517 aa (human)	573 aa (human)
Subtype Selective Agonist	SKF-89748 A-61603	Not Known	Not Known
Subtype Selective Antagonists	(+)-Niguldipine S-Methylurapidil (U101) Ro-70-0004 RS-17053	(±)-Cyclazosin (C247) L-765,314 (L3040)	BMY 7378 (B134)
Receptor Selective Agonists	Cirazoline (C223) Methoxamine (M6524) Phenylephrine (P6126)	Phenylephrine (P6126)	Methoxamine (M6524) Phenylephrine (P6126)
Receptor Selective Antagonists	Corynanthine Prazosin (P7791)	Corynanthine Prazosin (P7791)	Corynanthine Prazosin (P7791)
Signal Transduction Mechanisms	Gq/11 (increase IP3/DAG)	Gq/11 (increase IP3/DAG)	Gq/11 (increase IP3/DAG)
Radioligands of Choice	[3H]-Prazosin [125I]-HEAT [125I]-LY-762-459	[3H]-Prazosin [125I]-HEAT	[3H]-Prazosin [125I]-HEAT
Tissue Expression	Heart, liver, CNS, urogenital smooth muscle	Resistance vessels, spleen, kidney	Aorta, bladder, CNS
Physiological Function	Smooth muscle contraction, myocyte hypertrophy	Smooth muscle contraction, CNS stimulation	Smooth muscle contraction, locomotor activity
Disease Relevance	BPH, stress incontinence	Not Known	Overactive bladder

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

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