CCPA (biochemistry)

CCPA

Names
IUPAC name 2-Chloro-N6-cyclopentyladenosine
Systematic IUPAC name (2R,3R,4S,5R)-2-[2-Chloro-6-(cyclopentylamino)-9H-purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol
Identifiers
CAS Number	37739-05-2  Y
3D model (JSmol)	Interactive image
Abbreviations	CCPA
ChEMBL	ChEMBL284969  Y
ChemSpider	110356  Y
IUPHAR/BPS	374
MeSH	2-chloro-N(6)cyclopentyladenosine
PubChem CID	123807
CompTox Dashboard (EPA)	DTXSID00958774
InChI InChI=1S/C15H20ClN5O4/c16-15-19-12(18-7-3-1-2-4-7)9-13(20-15)21(6-17-9)14-11(24)10(23)8(5-22)25-14/h6-8,10-11,14,22-24H,1-5H2,(H,18,19,20)/t8-,10-,11-,14-/m1/s1 Y Key: XSMYYYQVWPZWIZ-IDTAVKCVSA-N Y InChI=1/C15H20ClN5O4/c16-15-19-12(18-7-3-1-2-4-7)9-13(20-15)21(6-17-9)14-11(24)10(23)8(5-22)25-14/h6-8,10-11,14,22-24H,1-5H2,(H,18,19,20)/t8-,10-,11-,14-/m1/s1 Key: XSMYYYQVWPZWIZ-IDTAVKCVBF
SMILES Clc1nc(c2ncn(c2n1)[C@@H]3O[C@@H]([C@@H](O)[C@H]3O)CO)NC4CCCC4
Properties
Chemical formula	C15H20ClN5O4
Molar mass	369.80 g/mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). Y  verify  (what is  YN ?) Infobox references

2-Chloro-N⁶-cyclopentyladenosine (CCPA) is a specific receptor agonist for the Adenosine A1 receptor. ^[1] It is similar to N⁶-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 [³H]CCPA 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 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 for A₁ adenosine receptors. In rat brain membranes, it demonstrated a K_i value of 0.4 nM, indicating potent interaction. Its selectivity is underscored by a significantly lower affinity for A_2A receptors, with a K_i value of 3,900 nM, reflecting nearly 10,000-fold selectivity for A₁ over A_2A. ^{[2] [3]}

Functional Effects

As an A₁ receptor agonist, CCPA effectively inhibits adenylate cyclase activity. In rat adipocyte membranes, it achieved an IC ₅₀ of 33 nM, demonstrating its potency. Conversely, its influence on A_2A 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 K_i 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. ^{[2] [4]}

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). In neurological 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. ^[5] 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

1. Karl-Norbert Klotz; Martin J. Lohse; Ulrich Schwabe; Gloria Cristalli; Sauro Vittori; Mario Grifantini (1989). "2-Chloro-N6-[3H]cyclopentyladenosine ([3HCCPA) — a high affinity agonist radioligand for A1 adenosine receptors". Naunyn-Schmiedeberg's Archives of Pharmacology. 340 (6): 679–683. doi:10.1007/BF00717744. PMID   2615857. S2CID   1114190.
2. Gao, Zhan-guo; Jacobson, Kenneth A. (May 2002). "2-Chloro-N6-cyclopentyladenosine, adenosine A1 receptor agonist, antagonizes the adenosine A3 receptor". European Journal of Pharmacology. 443 (1–3): 39–42. doi:10.1016/S0014-2999(02)01552-2. PMC   8358783 . PMID   12044789.
3. Cristalli, Gloria; Volpini, Rosaria; Vittori, Sauro; Camaioni, Emidio; Monopoli, Angela; Conti, Annamaria; Dionisotti, Silvio; Zocchi, Cristina; Ongini, Ennio (May 1994). "2-Alkynyl Derivatives of Adenosine-5'-N-ethyluronamide: Selective A2 Adenosine Receptor Agonists with Potent Inhibitory Activity on Platelet Aggregation" . Journal of Medicinal Chemistry. 37 (11): 1720–1726. doi:10.1021/jm00037a024. ISSN   0022-2623. PMID   8201607.
4. Lohse, MartinJ.; Klotz, Karl-Norbert; Schwabe, Ulrich; Cristalli, Gloria; Vittori, Sauro; Grifantini, Mario (June 1988). "2-Chloro-N6-cyclopentyladenosine: a highly selective agonist at A1 adenosine receptors" . Naunyn-Schmiedeberg's Archives of Pharmacology. 337 (6): 687–689. doi:10.1007/BF00175797. ISSN   0028-1298. PMID   3216901.
5. Fabera, Petr; Parizkova, Martina; Uttl, Libor; Vondrakova, Katerina; Kubova, Hana; Tsenov, Grygoriy; Mares, Pavel (2019-06-14). "Adenosine A1 Receptor Agonist 2-chloro-N6-cyclopentyladenosine and Hippocampal Excitability During Brain Development in Rats". Frontiers in Pharmacology. 10 656. doi: 10.3389/fphar.2019.00656 . ISSN   1663-9812. PMC   6587156 . PMID   31258477.