CCPA (biochemistry)
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2-Chloro-''N''6-cyclopentyladenosine (CCPA) is a specific
receptor agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the agon ...
for the
Adenosine A1 receptor The adenosine A1 receptor (A1AR) is one member of the adenosine receptor group of G protein-coupled receptors with adenosine as endogenous ligand. Biochemistry A1 receptors are implicated in sleep promotion by inhibiting wake-promoting choli ...
. It is similar to ''N''6-cyclopentyladenosine. Initially developed to probe the physiological and pharmacological roles of adenosine receptors, CCPA has become a pivotal tool in cardiovascular and neurological research. Due to CCPA's high affinity for Adenosine A1 receptors, its tritiated derivative sup>3HCPA can be used as a diagnostic tool for detecting the receptors in tissue with low receptor density.


Chemical Structure and Properties

CCPA is chemically characterized by the addition of a chlorine atom at the 2-position and a cyclopentyl group at the N6 position of the
adenosine Adenosine (symbol A) is an organic compound that occurs widely in nature in the form of diverse derivatives. The molecule consists of an adenine attached to a ribose via a β-N9- glycosidic bond. Adenosine is one of the four nucleoside build ...
molecule. These modifications enhance its receptor selectivity and binding affinity. The molecular formula of CCPA is C15H19ClN5O4, with a molecular weight of approximately 367.80 g/mol.


Pharmacological Profile


Affinity and Selectivity for Adenosine Receptors

CCPA exhibits a high
binding affinity In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. The etymology stems from Latin ''ligare'', which means 'to bind'. In protein-ligand binding, the ligand is usuall ...
for A1 adenosine receptors. In rat brain membranes, it demonstrated a Ki value of 0.4 nM, indicating potent interaction. Its selectivity is underscored by a significantly lower affinity for A2A receptors, with a Ki value of 3,900 nM, reflecting nearly 10,000-fold selectivity for A1 over A2A.


Functional Effects

As an A1 receptor
agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...
, CCPA effectively inhibits adenylate cyclase activity. In rat
adipocyte Adipocytes, also known as lipocytes and fat cells, are the cell (biology), cells that primarily compose adipose tissue, specialized in storing energy as fat. Adipocytes are derived from mesenchymal stem cells which give rise to adipocytes through ...
membranes, it achieved an IC50 of 33 nM, demonstrating its potency. Conversely, its influence on A2A receptors is minimal, requiring much higher concentrations to elicit comparable effects.


Interaction with A3 Adenosine Receptors

Interestingly, while CCPA acts as an agonist at A1 receptors, it functions as a moderate antagonist at human A3 adenosine receptors. Studies using Chinese hamster ovary cells expressing human A3 receptors revealed that CCPA binds with a Ki of 38 nM but does not activate the receptor. Instead, it competitively inhibits the effects of A3 receptor agonists, highlighting its dual role depending on the receptor subtype.


Applications in Biomedical Research

CCPA's selectivity and efficacy make it an invaluable tool in exploring adenosine receptor functions. In cardiovascular studies, it has been employed to investigate A1 receptor-mediated cardioprotective mechanisms, including modulation of heart rate and ischemic responses (
Ischemia Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems ...
). In
neurological Neurology (from , "string, nerve" and the suffix -logia, "study of") is the branch of medicine dealing with the diagnosis and treatment of all categories of conditions and disease involving the nervous system, which comprises the brain, the s ...
contexts, CCPA aids in elucidating the role of A1 receptors in neurotransmission and neuroprotection. Additionally, its antagonistic properties at A3 receptors provide insights into the complex interplay between different adenosine receptor subtypes. 2-Chloro-N6-cyclopentyladenosine (CCPA) stands out as a potent and selective adenosine A1 receptor agonist with unique antagonistic effects on A3 receptors. Its distinct chemical structure underpins its receptor specificity, rendering it a crucial compound in cardiovascular and neurological research. Ongoing studies continue to uncover its potential therapeutic applications and deepen our understanding of adenosine receptor pharmacology.


References

Nucleosides Purines Organochlorides Adenosine receptor agonists Cyclopentyl compounds {{nervous-system-drug-stub