The alpha-2 (α2) adrenergic receptor is a G protein-coupled receptor (GPCR) associated with the Gi heterotrimeric G-protein. It consists of three highly homologous subtypes, including α2A-, α2B-, and α2C-adrenergic. Some species other than humans express a fourth α2D-adrenergic receptor as well. Catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline) signal through the α2-adrenergic receptor in the central and peripheral nervous systems.
Phenyltropanes (PTs) were originally developed to reduce cocaine addiction and dependency. In general these compounds act as inhibitors of the plasmalemmal monoamine reuptake transporters. Although RTI holds a strong position in this field, they are not the only researchers that have prepared these analogues. This research has spanned beyond the last couple decades, and has picked up its pace in recent times, creating numerous phenyltropanes as research into cocaine analogues garners interest to treat addiction.
Alpha-adrenergic agonists are a class of sympathomimetic agents that selectively stimulates alpha adrenergic receptors. The alpha-adrenergic receptor has two subclasses α1 and α2. Alpha 2 receptors are associated with sympatholytic properties. Alpha-adrenergic agonists have the opposite function of alpha blockers. Alpha adrenoreceptor ligands mimic the action of epinephrine and norepinephrine signaling in the heart, smooth muscle and central nervous system, with norepinephrine being the highest affinity. The activation of α1 stimulates the membrane bound enzyme phospholipase C, and activation of α2 inhibits the enzyme adenylate cyclase. Inactivation of adenylate cyclase in turn leads to the inactivation of the secondary messenger cyclic adenosine monophosphate and induces smooth muscle and blood vessel constriction.
Medetomidine is a synthetic drug used as both a surgical anesthetic and analgesic. It is often used as the hydrochloride salt, medetomidine hydrochloride, a crystalline white solid. It is an α2 adrenergic agonist that can be administered as an intravenous drug solution with sterile water.
The alpha-2C adrenergic receptor, also known as ADRA2C, is an alpha-2 adrenergic receptor, and also denotes the human gene encoding it.
The alpha-1A adrenergic receptor, also known as ADRA1A, formerly known also as the alpha-1C adrenergic receptor, is an alpha-1 adrenergic receptor, and also denotes the human gene encoding it. There is no longer a subtype α1C receptor. At one time, there was a subtype known as α1C, but it was found to be identical to the previously discovered α1A receptor subtype. To avoid confusion, the naming convention was continued with the letter D.
AM-906 (part of the AM cannabinoid series) is an analgesic drug which is a cannabinoid agonist. It is conformationally restricted by virtue of the double bond on its side chain, leading an increased affinity for and selectivity between CB1 and CB2 receptors. It is a potent and selective agonist for the CB1 cannabinoid receptor, with a Ki of 0.8 nM at CB1 and 9.5 nM at CB2, a selectivity of almost 12x.
AM-905 (part of the AM cannabinoid series) is an analgesic drug which is a cannabinoid agonist. It is conformationally restricted by virtue of the double bond on its side chain, leading an increased affinity for and selectivity between CB1 and CB2 receptors. It is a potent and reasonably selective agonist for the CB1 cannabinoid receptor, with a Ki of 1.2 nM at CB1 and 5.3 nM at CB2.
Alpha-2 blockers are a subset of the alpha blocker class of drugs and are antagonists to the α2 adrenergic receptor. They are mainly used in research, having found limited clinical application in human medicine. Alpha-2 blockers increase noradrenaline release.
Efaroxan is an α2-adrenergic receptor antagonist and antagonist of the imidazoline receptor.
TPA-023 (MK-0777) is an anxiolytic drug with a novel chemical structure, which is used in scientific research. It has similar effects to benzodiazepine drugs, but is structurally distinct and so is classed as a nonbenzodiazepine anxiolytic. It is a subtype-selective, mixed allosteric modular at the benzodiazepine location on GABAA receptors, where it acts as a partial agonist at the α2 and α3 subtypes, but as a silent antagonist at α1 and α5 subtypes. It has primarily anxiolytic and anticonvulsant effects in animal tests, but with no sedative effects even at 50 times the effective anxiolytic dose.
SB-269970 is a drug and research chemical developed by GlaxoSmithKline used in scientific studies. It is believed to act as a selective 5-HT7 receptor antagonist (EC50 = 1.25 nM) (or possibly inverse agonist). A subsequent study in guinea pig at a concentration of 10 μM showed that it also blocks the α2-adrenergic receptor. The large difference in test concentrations however confirms the selectivity of SB-269970 for the 5-HT7 receptor.
(R)-3-Nitrobiphenyline is a drug which acts as an α2-adrenergic agonist, selective for the α2C subtype, as well as being a weak antagonist at the α2A and α2B subtypes. It has been used in scientific research to characterize the binding and functional properties of the α2C subtype.
Imiloxan is a drug which is used in scientific research. It acts as a selective antagonist for the α2B adrenergic receptor, and has been useful for distinguishing the actions of the different α2 adrenergic subtypes.
Doxanthrine is a synthetic compound which is a potent and selective full agonist for the dopamine D1 receptor. Doxanthrine has been shown to be orally active in producing contralateral rotation in the 6-hydroxydopamine rat model of Parkinson's disease.
L-765,314 is a drug which acts as a potent and selective antagonist of the α1-adrenergic receptor subtype α1B. It has mainly been used to investigate the role of α1B-adrenergic receptors in the regulation of blood pressure. The α1B receptor is also thought to have an important role in the brain; however, L-765,314 does not cross the blood–brain barrier.
6-Fluoronorepinephrine (6-FNE) is a selective α1- and α2-adrenergic receptor full agonist related to norepinephrine. It is the only selective full agonist for the α-adrenergic receptors known to date and has been used to study their function in scientific research. Infusion of 6-FNE into the locus coeruleus of rodents produces marked hyperactivity and behavioral disinhibition by suppressing activity in the area via stimulation of α1-adrenergic receptors.
Aptazapine (developmental code name CGS-7525A) is a tetracyclic antidepressant (TeCA) that was assayed in clinical trials for the treatment of depression in the 1980s but was never marketed. It is a potent α2-adrenergic receptor antagonist with ~10x the strength of the related compound mianserin and has also been shown to act as a 5-HT2 receptor antagonist and H1 receptor inverse agonist, while having no significant effects on the reuptake of serotonin or norepinephrine. Based on its pharmacological profile, aptazapine may be classified as a noradrenergic and specific serotonergic antidepressant (NaSSA).
WB-4101 is a compound which acts as an antagonist at the α1B-adrenergic receptor. It was one of the first selective antagonists developed for this receptor and was invented in 1969, but is still commonly used in research into adrenergic receptors, especially as a lead compound from which to develop more selective drugs.
1-Methyl-3-propyl-4-(p-chlorophenyl)piperidine is a drug developed by a team led by Alan Kozikowski, which acts as a potent dopamine reuptake inhibitor, and was developed as a potential therapeutic agent for the treatment of cocaine addiction. As with related compounds such as nocaine, it is a structurally simplified derivative of related phenyltropane compounds. Its activity at the serotonin and noradrenaline transporters has not been published, though most related 4-phenylpiperidine derivatives are relatively selective for inhibiting dopamine reuptake over the other monoamine neurotransmitters. While several of its isomers are active, the (3S,4S)-enantiomer is by far the most potent. The rearranged structural isomer 2-[1-(4-chlorophenyl)butyl]piperidine is also a potent inhibitor of dopamine reuptake.
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