α2-Adrenoceptors are widely distributed and are activated by norepinephrine (A7257, A0937), released from sympathetic nerve terminals or by epinephrine (E4250, E4375), released from the adrenal medulla and from some neurons in the CNS. Perhaps the most extensively characterized action is the prejunctionally mediated inhibition of the release of neurotransmitter from many peripheral and central neurons. Activation of prejunctional autoreceptors on sympathetic neurons results in a sympatholytic action. α2-Adrenoceptors are also present at postjunctional sites, where they mediate actions such as smooth muscle contraction, platelet aggregation and inhibition of insulin secretion. Activation of postsynaptic α2-adrenoceptors in the brainstem results in an inhibition of sympathetic outflow to the periphery. Many α2-adrenoceptor mediated effects are mediated via inhibition of adenylyl cyclase as a consequence of interaction of the agonist-receptor complex with Gi, although other second messengers remain to be characterized.
Three α2-adrenoceptor proteins have been cloned. These recombinant receptors, designated as α2a, α2b and α2c, result in four discrete pharmacological profiles, since the α2a adrenoceptor appears to exist as species orthologs, with those of human, pig and rabbit having a profile designated as α2A, while those of rat, mouse, guinea-pig and cow exhibit pharmacology designated as α2D. α2A and α2D mediated responses can be differentiated by the low sensitivity of the α2D adrenoceptor to blockade by the commonly used antagonists yohimbine and rauwolscine.
The α2A or α2D subtype (depending on species) appears to be responsible for most α2-adrenoceptor mediated responses. This includes the major component of prejunctional modulation of sympathetic neurotransmission and central sympathoinhibitory activity, although all three subtypes may contribute. Gene knockout experiments support this premise, but show that, at least in mice, the initial pressor action of an α2-adrenoceptor agonist results from activation of the α2B adrenoceptor. While knockout of the α2c adrenoceptor has no apparent cardiovascular effects, elimination of both α2a and α2c adrenoceptors results in complete loss of prejunctional modulation of adrenergic neurotransmission and induces pathologic effects related to excess adrenergic tone. The α2C adrenoceptor mediates cold-induced augmentation of α-adrenoceptor induced vasoconstriction, which may involve translocation of receptors from intracellular sites to the plasma membrane. Overexpression and knockout experiments suggest that the α2C adrenoceptor may have important functions in the CNS.
Selective α2-adrenoceptor agonists are used for the treatment of hypertension; their sedative and analgesic activity has also led to their use as adjuncts to general anesthesia. Other applications for central α2-adrenoceptor activation include opiate withdrawal, attention deficit hyperactivity disorder and Tourette's syndrome. Intra-ocular administration of an α2-adrenoceptor agonist will reduce intra-ocular pressure in glaucoma. None of the agonists employed clinically show pharmacologically significant selectivity between the α2-adrenoceptor subtypes.
The Table below contains accepted modulators and additional information. Compare these modulators as well as several similar products (A0232, A9611, SML0460, SML0675) in the "All Products" section that follows.
a) The α2A and α2D are pharmacologically distinct, but are genetic orthologs. The α2A is found in the human, pig and rabbit, whereas the α2D is found in the rat, mouse and cow.
ARC 239: (2-[2-[4-(o-Methoxyphenyl)piperazin-1-yl]ethyl]-4,4-dimethyl-1,3-(2H,4H)-isoquinolinedione
BHT 920: 5,6,7,8-Tetrahydro-6-(2-propenyl)-4H-thiazolo[4,5-d]-azepine-2-amine
BHT 933: 6-Ethyl-5,6,7,8-tetrahydro-4H-oxazolo[4,5-d]azepin-2-amine
BRL 44408: (2-[2H-(1-Methyl-1,3-dihydroisoindole)methyl]-4,5-dihydroimidazole
RX 821002: 2-Methoxy-idazoxan
UK 14,304: 5-Bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine