CCPA (biochemistry)

Last updated
CCPA
2-Chloro-N(6)cyclopentyladenosine.svg
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
3D model (JSmol)
AbbreviationsCCPA
ChEMBL
ChemSpider
MeSH 2-chloro-N(6)cyclopentyladenosine
PubChem CID
  • 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 Yes check.svgY
    Key: XSMYYYQVWPZWIZ-IDTAVKCVSA-N Yes check.svgY
  • 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
  • Clc1nc(c2ncn(c2n1)[C@@H]3O[C@@H]([C@@H](O)[C@H]3O)CO)NC4CCCC4
Properties
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).
Yes check.svgY  verify  (what is  Yes check.svgYX mark.svgN ?)

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.

Contents

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 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. [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 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. [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. 1 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). doi:10.1007/BF00175797. ISSN   0028-1298.
  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.