A2-Adrenoreceptors

Some alkaloids are active in a and /3-adrenergic receptors (e.g. ephedrine), a receptors (e.g. ergotamine), uterine a2 receptors (e.g. ergometrine) or presy-naptic a2 adrenoreceptors (e.g. yohimbine). Ephedrine increases blood pressure... 

Ergotamine blocks a receptors. It has an inhibitory effect on the cardiovascular system. Ergometrine also has a high affinity to uterine a2 receptors, and it therefore influences uterine muscle activity. Ergometrine is used in the treatment of postpartum or postbortal haemorrhaging. Yohimbine blocks presynaptic a2 adrenoreceptors and increases the release of noradrenaline at sympathetic nerve endings. It may be used to increase heart rate and blood pressure and even in the treatment of severe cases of male impotency. 

Pralong, E. and Magistretti, P.J. (1995) Norepinephrine increases K-conductance and reduces gluramatergic transmission in the mouse entorhinal cortex by activation of a2-adrenoreceptors. Eur J Neurosci 7 2370-2378. 

Szot P, Lester M, Laughlin ML, Palmiter RD, Liles LC, Weinshenker D (2004) The anticonvulsant and proconvulsant effects of a2-adrenoreceptor agonists are mediated by distinct populations of a2A-adrenoreceptors. Neuroscience 126 795-803... 

There are two principal groups of receptors for epinephrine and NE, so-called adrenoreceptors, which are divided into a- and P-adrenoreceptors. a-adrenoreceptors are subdivided into oti and oc2, whereas the P-adrenoreceptors into Pi, P2 and P3. All the adrenoreceptors are coupled to different G protein subtypes. More specifically, oci-adrenoreceptors is coupled to Gq, a2-adrenoreceptors to Gi, and all the P-adrenoreceptors to Gs. Briefly, activation of Gs and G, stimulates and reduces the production of cAMP, respectively. cAMP functions as a second messenger that can activate the protein kinase A (PKA), which in turn, can transfer the signals to the nucleus. 

On the other hand, a2-adrenoreceptors mostly mediate their intracellular signalling through G,. In this case, the signalling through the Ga and Gpy subunits may be important. Activation of the Gm leads to the inhibition of adenylyl cyclase (AC) with a reduction in cAMP levels, whereas activation of Gpy leads to inhibition of Ca2+ channels and activation of K+ channels and mitogen-activated protein kinases MAPK (Hein et al., 2006). 

Blockade of a2, Pi and p2-adrenoreceptors on LPS-stimulated alveolar macrophages reduces the release of interleukin (IL)-ip, IL-6 and cytokine-induced neutrophil chemoattractant-1. In this same condition, TNFa release is also strongly reduced by a2 and p2-adrenoreceptors antagonists. However, the blockade of a2-adrenoreceptors reached the most consistent suppression of the investigated cytokines (Flierl et al., 2007). 

The remaining neurons of the LC seem to dampen NE deficiency by several mechanisms by increase in tyrosine hydroxylase mRNA expression and metabolic activity, and sprouting of axons into the hippocampus as evidenced by an increase in a2-adrenoreceptors (Szot et al., 2006) (Hoogendijk et al., 1999). However, an overall decrease in a2-adrenoreceptor density in the brain of AD patients has been described (Meana et al., 1992). Moreover, a reduced density of NE innervation into the hippocampus has been observed (Powers et al., 1988). 

Acute oral administration of amitraz causes central nervous system (CNS) depression. The toxic effects of amitraz are possibly from a2-adrenoreceptor agonist action. Chronic exposure of amitraz results in CNS depression, increases blood glucose levels, and produces hypothermia. 

Other Agents. Phentolamine is a nonselective al- and a2-adrenoreceptor antagonist. It is a weak erectogenic agent when used alone as an intracavemosal injection. Phentolamine is usually used in combination with alprostadil and/or papaverine. 

Winzer-Serhan UH, Raymon HK, Broide RS, Chen Y, Leslie FM. 1997a. Expression of a2 adrenoreceptors during rat brain development- . a2A messenger RNA expression. Neuroscience 76 241-260. 

Antagonist affinities of tetraamine disulfides at ai- and a2 adrenoreceptors in the isolated rat vas deferens, and for inhibiting pH]prazosin binding at ai-adrenoreceptor subtypes of rat submaxillary gland (oia) and liver (oib)... 

Dantrolene has a direct action on skeletal muscle to cause relaxation baclofen inhibits transmission at the spinal cord by acting on inhibitory presynaptic gamma-aminobutyric acid B (GABAb) receptors benzodiazepines cause muscle relaxation by some central action and tizanidine is an a2 adrenoreceptor agonist presumably with a central action. 

Noradrenergic a2-adrenoreceptor Dopaminergic type D2 histamine type 3 (H3) muscarinic type 2 (M2) opiate P2-adrenoreceptor Nicotinic... 

Other intracorporal agents used to induce penile erections include papaverine, a drug with a relaxant effect on smooth muscle, and phentolamine, an a-adrenergic receptor blocker. Yohimbine, an a2-adrenoreceptor antagonist, enhances noradrenergic neurotransmission and may improve erectile dysfunction via adrenergic system activation. 

Catechol (22) was treated with 2-chloroacrylonitrile in basic conditions Michael addition to one OH group followed by a Williamson s reaction onto the other gave the nitrile (23) which was elaborated on to idazoxan (24) Scheme 5.7.) [14, 15]. It is claimed to be one of the most potent and selective a2-adrenergic receptor antagonists [16-19], Idazoxan shows unusual differential binding to a2-adrenoreceptors of different species [20]... 

The racemic phenoxymethylimidazoline lofexidine (44) is unusual among the imidazolines in having a2-adrenoreceptor agonist activity it is used as an antihypertensive and is similar in potency to clonidine (133) [52]. The route of preparation is shown in Scheme 5.12. Resolution of (44) with (-)-dibenzoyltartaric acid gave the enantiomers levlofexidine [(-)-lofexidine] (52) and dexlofexidine [(+)-lofexidine] (53) [53]. 

Some alkaloids are active in a- and p-adrenergic receptors (e.g., ephedrine), a receptors (e.g., ergotamine), uterine a2 receptors (e.g., ergometrine), and presynaptic a2 adrenoreceptors (e.g., yohombine). Ephedrine increases blood pressure by elevating cardiac output. It is also known to have some stimulant activity on the respiratory center. Ephedrine may be applied in the treatment of eczema in insulin-dependent diabetics. Clonidine stimulates tt2 receptors in the brain. As the effect of this, the cardiac output is smaller and blood pressure is lowered. Clonidine as an 0(2 adrenergic receptor agonist improves endothelial function and modulates inflammation during reperfusion." ... 

Efaroxan, an a2 adrenoreceptor antagonist, could be used for the treatment of neurodegenerative diseases (Alzheimer and Parkinson), migraine and type II diabetes. Therefore, the total syntheses of ( + )-efaroxan and their derivatives have drawn much attention.The chiral 2,3-dihydrobenzofuran carboxylic acid 135, the direct precursor of (+ )-efaroxan, was obtained mainly from the resolution of racemic 135. Coelho el al. have reported a straightforward enantioselective synthesis of i -( + )-2-ethyl-2,3-dihydrofuran-2-carboxylic acid (135) achieved by a Sharpless-Katsuki asymmetric epoxidation reaction (Scheme 5.22). The dihydrobenzofuran acid 135 was obtained in seven steps from MBH adduct 136 in an overall yield of 17%. 

Goldberg MR, Robertson D (1983) Yohimbine - a Pharmacological Probe for Study of the a2-Adrenoreceptor. Pharmacol Rev 35 143... 

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