Alpha-2 adrenergic receptor

See also: Adrenergic receptor

The alpha-2 (α₂) adrenergic receptor (or adrenoceptor) is a G protein-coupled receptor (GPCR) associated with the G_i heterotrimeric G-protein. It consists of three highly homologous subtypes, including α_2A-, α_2B-, and α_2C-adrenergic. Some species other than humans express a fourth α_2D-adrenergic receptor as well. Catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline) signal through the α₂-adrenergic receptor in the central and peripheral nervous systems.

Cellular localisation

The α_2A adrenergic receptor is localised in the following central nervous system (CNS) structures:

• Brainstem (especially the locus coeruleus)
• Midbrain
• Hypothalamus
• Hippocampus
• Spinal cord
• Cerebral cortex
• Cerebellum
• Septum

Whereas the α_2B adrenergic receptor is localised in the following CNS structures:

• Olfactory system
• Thalamus
• Pyramidal layer of the hippocampus
• Cerebellar purkinje layer

and the α_2C adrenergic receptor is localised in the CNS structures:

• Midbrain
• Thalamus
• Amygdala
• Dorsal root ganglia
• Olfactory system
• Hippocampus
• Cerebral cortex
• Basal ganglia
• Substantia nigra
• Ventral tegmentum

Effects

The α₂-adrenergic receptor is classically located on vascular prejunctional terminals where it inhibits the release of norepinephrine (noradrenaline) in a form of negative feedback. It is also located on the vascular smooth muscle cells of certain blood vessels, such as those found in skin arterioles or on veins, where it sits alongside the more plentiful α₁-adrenergic receptor. The α₂-adrenergic receptor binds both norepinephrine released by sympathetic postganglionic fibers and epinephrine (adrenaline) released by the adrenal medulla, binding norepinephrine (noradrenaline) with slightly higher affinity. It has several general functions in common with the α₁-adrenergic receptor, but also has specific effects of its own. Agonists (activators) of the α₂-adrenergic receptor are frequently used in veterinary anaesthesia where they affect sedation, muscle relaxation and analgesia through effects on the central nervous system (CNS).

General

Common effects include:

• Suppression of release of norepinephrine (noradrenaline) by negative feedback.
• Transient hypertension (increase in blood pressure), followed by a sustained hypotension (decrease in blood pressure).
• Vasoconstriction of certain arteries
• Vasoconstriction of arteries to heart (coronary artery); however, the extent of this effect may be limited and may be negated by the vasodilatory effect from β₂ receptors
• Constriction of some vascular smooth muscle
• Venoconstriction of veins
• Decrease motility of smooth muscle in gastrointestinal tract
• Inhibition of lipolysis
• Facilitation of the cognitive functions associated with the prefrontal cortex (PFC; working memory, attention, executive functioning, etc.)
• Sedation
• Analgesia

Individual

Individual actions of the α₂ receptor include:

• Mediates synaptic transmission in pre- and postsynaptic nerve terminals
  • Decrease release of acetylcholine
  • Decrease release of norepinephrine
    • Inhibit norepinephrine system in brain
• Inhibition of lipolysis in adipose tissue
• Inhibition of insulin release in pancreas
• Induction of glucagon release from pancreas
• platelet aggregation
• Contraction of sphincters of the gastrointestinal tract
• Decreased secretion from salivary gland
• Relax gastrointestinal tract (presynaptic effect)
• Decreased aqueous humor fluid production from the ciliary body

Signaling cascade

The α subunit of an inhibitory G protein - G_i dissociated from the G protein, and associates with adenylyl cyclase. This causes the inactivation of adenylyl cyclase, resulting in a decrease of cAMP produced from ATP, which leads to a decrease of intracellular cAMP. PKA is not able to be activated by cAMP, so proteins such as phosphorylase kinase cannot be phosphorylated by PKA. In particular, phosphorylase kinase is responsible for the phosphorylation and activation of glycogen phosphorylase, an enzyme necessary for glycogen breakdown. Thus in this pathway, the downstream effect of adenylyl cyclase inactivation is decreased breakdown of glycogen.

The relaxation of gastrointestinal tract motility is by presynaptic inhibition, where transmitters inhibit further release by homotropic effects.

Ligands

Agonists

• 4-NEMD
• 7-Me-marsanidine (also I₁ agonist)
• Agmatine (also I agonist, NMDA, 5-HT3, nicotinic antagonist and NOS inhibitor)
• Apraclonidine
• Brimonidine
• Cannabigerol (also acts as a moderate affinity 5-HT1A receptor agonist, and low affinity CB1 receptor antagonist).
• Clonidine (also I₁ agonist)
• Detomidine
• Dexmedetomidine
• Fadolmidine
• Guanabenz
• Guanfacine
• Lofexidine
• Marsanidine
• Medetomidine
• Methamphetamine
• Mivazerol
• Rilmenidine (also I agonist)
• Romifidine
• Talipexole (also dopamine agonist)
• Tiamenidine
• Tizanidine
• Tolonidine
• Xylazine
• Xylometazoline

Partial agonists

• Oxymetazoline (also α1 agonist)
• TDIQ

Antagonists

• Aripiprazole
• Asenapine
• Atipamezole
• Cirazoline
• Clozapine
• Efaroxan
• Idazoxan
• Lurasidone
• Melperone
• Mianserin
• Mirtazapine
• Napitane
• Olanzapine
• Paliperidone (also primary active metabolite of Risperidone)
• Phenoxybenzamine
• Phentolamine
• Piribedil
• Rauwolscine
• Risperidone
• Rotigotine (α_2B antagonist, non-selective)
• Quetiapine
• Norquetiapine (primary active metabolite of Quetiapine)
• Setiptiline
• Tolazoline
• Yohimbine
• Ziprasidone
• Zotepine (discontinued)

Binding affinity (K_i in nM) and clinical data on a number of alpha-2 ligands

Drug	α1A	α1B	α1D	α2A	α2B	α2C	Indication(s)	Route of Administration	Bioavailability	Elimination half-life	Metabolising enzymes	Protein binding
Agonists
Clonidine	316.23	316.23	125.89	42.92	106.31	233.1	Hypertension, ADHD, analgesia, sedation	Oral, epidural, transdermal	75-85% (IR), 89% (XR)	12-16 h	?	20-40%
Dexmedetomidine	199.53	316.23	79.23	6.13	18.46	37.72	Procedural and ICU sedation	IV	100%	6 minutes		94%
Guanfacine	?	?	?	71.81	1200.2	2505.2	Hypertension, ADHD	Oral	80-100% (IR), 58% (XR)	17 h (IR), 18 h (XR)	CYP3A4	70%
Xylazine	?	?	?	5754.4	3467.4	>10000	Veterinary sedation	?	?	?	?	?
Xylometazoline	?	?	?	15.14	1047.13	128.8	Nasal congestion	Intranasal	?	?	?	?
Antagonists
Asenapine	1.2	?	?	1.2	0.32	1.2	Schizophrenia, bipolar disorder	Sublingual	35%	24 h	CYP1A2 & UGT1A4	95%
Clozapine	1.62	7	?	37	25	6	Treatment-resistant schizophrenia	Oral	50-60%	12 h	CYP1A2, CYP3A4, CYP2D6	97%
Mianserin	74	?	?	4.8	27	3.8	Depression	Oral	20%	21-61 h	CYP3A4	95%
Mirtazapine	500	?	?	20	?	18	Depression	Oral	50%	20-40 h	CYP1A2, CYP2D6, CYP3A4	85%

Agonists

Norepinephrine has higher affinity for the α₂ receptor than has epinephrine, and therefore relates less to the latter's functions. Nonselective agonists include the antihypertensive drug clonidine, used to lower blood pressure and hot flashes associated with menopausal symptoms. Clonidine has also been successfully used in indications that exceed what would be expected from a simple blood-pressure lowering drug: it has recently shown positive results in children with ADHD who suffer from tics resulting from the treatment with a CNS stimulant drug, such as Adderall XR or methylphenidate; clonidine also helps alleviate symptoms of opioid withdrawal. The hypotensive effect of clonidine was initially attributed through its agonist action on presynaptic α₂ receptors, which act as a down-regulator on the amount of norepinephrine released in the synaptic cleft, an example of autoreceptor. However, it is now known that clonidine binds to imidazoline receptors with a much greater affinity than α₂ receptors, which would account for its applications outside the field of hypertension alone. Imidazoline receptors occur in the nucleus tractus solitarii and also the centrolateral medulla. Clonidine is now thought to decrease blood pressure via this central mechanism. Other nonselective agonists include dexmedetomidine, lofexidine (another antihypertensive), TDIQ (partial agonist), tizanidine (in spasms, cramping) and xylazine. Xylazine has veterinary use.

In the European Union, dexmedetomidine received a marketing authorization from the European Medicines Agency (EMA) on 08/10/2012 under the brand name of Dexdor. It is indicated for sedation in the ICU for patients needing mechanical ventilation.

In non-human species this is an immobilizing and anesthetic drug, presumptively also mediated by α₂ adrenergic receptors because it is reversed by yohimbine, an α₂ antagonist.

α_2A selective agonists include guanfacine (an antihypertensive) and Brimonidine (UK 14,304).

(R)-3-nitrobiphenyline is an α_2C selective agonist.

Antagonists

Nonselective α blockers include, A-80426, atipamezole, phenoxybenzamine, efaroxan, idazoxan*(experimental), SB-269,970 and yohimbine* (a treatment for erectile dysfunction).

Tetracyclic antidepressants mirtazapine and mianserin are also potent α antagonists with mirtazapine being more selective for α₂ subtype (~30-fold selective over α₁) than mianserin (~17-fold).

α_2A selective blockers include BRL-44408 and RX-821,002.

α_2B selective blockers include ARC-239 and imiloxan.

α_2C selective blockers include JP-1302 and spiroxatrine, the latter also being a serotonin 5-HT_1A antagonist.

See also

• Adrenergic receptor