Recettori per l'adenosina: differenze tra le versioni

Da Wikipedia, l'enciclopedia libera.
Vai alla navigazione Vai alla ricerca
Differenza successiva →
Contenuto cancellato Contenuto aggiunto
VisualeWikitesto
←Nuova pagina: I '''recettori per l'adenosina''' (or '''recettori P1'''<ref name="pmid9133776">{{cite journal | author = Fredholm BB, Abbracchio MP, Burnstock G, Dubyak GR, Harden TK...
(Nessuna differenza)

Versione delle 10:36, 7 nov 2009

I recettori per l'adenosina (or recettori P1[1]) sono una classe di recettori purinergici, recettori accoppiati alle proteine G che hanno nell'adenosina il ligando endogeno .[2]

Farmacolgia

Nell'uomo, ci sono quattro recettori per l'adenosina. ognuno di essi è codificato da un gene ed ha diverse funzioni, malgrado ve ne siano alcune in comune.[3] Pe resempio, sia il recettore A1 che il recettore A2A esercitano un ruolo importante nella fisiologia cardiaca, regolando il consumo di ossigeno del miocardio ed il flusso nelle arterie coronarie, mentre il il recettore A2A media anche risposte anti-infiammatorie nell'organismo.[4] Questi due recettori rivestono ruoli importanti anche nella fisiologia dell'encefalo,[5] regolando il rilascio di altri neurotransmettitori, come la dopamina ed il glutammato,[6][7][8] while the A2B ed i recettori A3 sono distribuiti prevalentemente in periferia e sono coinvoltiin processi come l'infiammazione e la risposta immunitaria.

La gran parte delle vecchie molecole che agisce sui recettori per l'adenosina è non selettiva, come ad esempio l'adenosina stessa, usata tuttora per il trattamento delle tachicardie (ritmo rapido del cuore),[9] e che interagisce con tutti i quattro recettori nel cuore,[10] e che produce un effetto sedativo attraverso i recettori A1 e A2A distribuiti nell'encefalo. i derivati della Xantina, come la caffeina e la teofillina agiscono come antagonista (pharmacology) non selettivo sui recettori A1 e A2A sia nel cuore che nell'encefalo, determinado un effetto stimolante e tachicardia.[11] Queste molecole agiscono anche come inibitori delle fosfodiesterasi e producono anche effetti antiinflammatori, rendendosi utili nel trattamento farmacologico dell'asma, ma meno adatti a scopi d iricerca.[12]

I nuvi agonisti ed antagonisti del recettore per l'adenosina sono molto più potenti e selettivi, ed hanno permesso di approfondire l'effetto del blocco o della stimolazione dei singoli sottotipi di recettori, dando luogo poi ad una nuova generazione di molecole utili in campo medico. Alcune di queste molecole sono ancora derivatai dell'adenosina odella xantina , ma i ricercatori hanno scoperto altr emolecole con struttura completamente diversa.[13][14]

Confronto dei sottotipi recettoriali

Adenosine receptors
Receptor Gene Mechanism [15] Effects Agonists Antagonists
A1 ADORA1 Gi/o --> cAMP↑/↓
A2A ADORA2A Gs --> cAMP↑
A2B ADORA2B Gs --> cAMP↑
  • bronchospasm
A3 ADORA3 Gi/o -->
  • 2-(1-Hexynyl)-N-methyladenosine
  • CF-101 (IB-MECA)
  • 2-Cl-IB-MECA
  • CP-532,903
  • MRS-3558
  • theophylline
  • MRS-1191
  • MRS-1220
  • MRS-1334
  • MRS-1523
  • MRS-3777
  • MRE3008F20
  • PSB-10
  • PSB-11
  • VUF-5574

A1 adenosine receptor

Lo stesso argomento in dettaglio: Adenosine A1 receptor.

The adenosine A1 receptor has been found to be ubiquitous throughout the entire body.

Mechanism

This receptor has an inhibitory function on most of the tissues in which it rests. In the brain, it slows metabolic activity by a combination of actions. Presynaptically, it reduces synaptic vesicle release while post synaptically it has been found to stabilize the magnesium on the NMDA receptor.

Antagonism and agonism

Specific A1 antagonists include 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX), and Cyclopentyltheophylline‎ (CPT) or 8-cyclopentyl-1,3-dipropylxanthine‎ (CPX), while specific agonists include 2-chloro-N(6)-cyclopentyladenosine (CCPA).

In the heart

The A1, together with A2A receptors, of endogenous adenosine are believed to play a role in regulating myocardial oxygen consumption and coronary blood flow. Stimulation of the A1 receptor has a myocardial depressant effect by decreasing the conduction of electrical impulses and suppressing pacemaker cell function, resulting in a decrease in heart rate. This makes adenosine a useful medication for treating and diagnosing tachyarrhythmias, or excessively fast heart rates. This effect on the A1 receptor also explains why there is a brief moment of cardiac standstill when adenosine is administered as a rapid IV push during cardiac resuscitation. The rapid infusion causes a momentary myocardial stunning effect.

In normal physiological states, this serves as protective mechanisms. However, in altered cardiac function, such as hypoperfusion caused by hypotension, heart attack or cardiac arrest caused by nonperfusing bradycardias, adenosine has a negative effect on physiological functioning by preventing necessary compensatory increases in heart rate and blood pressure that attempt to maintain cerebral perfusion.

In neonatal medicine

Adenosine antagonists are widely used in neonatal medicine;

Because a reduction in A1 expression appears to prevent hypoxia-induced ventriculomegaly and loss of white matter and therefore raise the possibility that pharmacological blockade of A1 may have clinical utility.

Theophylline and caffeine are nonselective adenosine antagonists that are used to stimulate respiration in premature infants.

A2A adenosine receptor

Lo stesso argomento in dettaglio: Adenosine A2A receptor.

As with the A1, the A2A receptors are believed to play a role in regulating myocardial oxygen consumption and coronary blood flow.

Mechanism

The activity of A2A adenosine receptor, a G-protein coupled receptor family member, is mediated by G proteins which activate adenylyl cyclase. It is abundant in basal ganglia, vasculature and platelets and it is a major target of caffeine.[16]

Function

The A2A receptor is responsible for regulating myocardial blood flow by vasodilating the coronary arteries, which increases blood flow to the myocardium, but may lead to hypotension. Just as in A1 receptors, this normally serves as a protective mechanism, but may be destructive in altered cardiac function.

Agonists and antagonists

Specific antagonists include istradefylline (KW-6002) and SCH-58261, while specific agonists include CGS-21680 and ATL-146e.[17]

A2B adenosine receptor

Lo stesso argomento in dettaglio: Adenosine A2B receptor.

This integral membrane protein stimulates adenylate cyclase activity in the presence of adenosine. This protein also interacts with netrin-1, which is involved in axon elongation.

A3 adenosine receptor

Lo stesso argomento in dettaglio: Adenosine A3 receptor.

It has been shown in studies to inhibit some specific signal pathways of adenosine. It allows for the inhibition of growth in human melanoma cells. Specific antagonists include MRS1191, MRS1523 and MRE3008F20, while specific agonists include Cl-IB-MECA and MRS3558.[17]

References

  1. ^ Fredholm BB, Abbracchio MP, Burnstock G, Dubyak GR, Harden TK, Jacobson KA, Schwabe U, Williams M, Towards a revised nomenclature for P1 and P2 receptors, in Trends Pharmacol. Sci., vol. 18, n. 3, 1997, pp. 79–82, DOI:10.1016/S0165-6147(96)01038-3.
  2. ^ Fredholm BB, IJzerman AP, Jacobson KA, Klotz KN, Linden J, International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors, in Pharmacol. Rev., vol. 53, n. 4, 2001, pp. 527–52.
  3. ^ Gao ZG, Jacobson KA, Emerging adenosine receptor agonists, in Expert Opinion on Emerging Drugs, vol. 12, n. 3, September 2007, pp. 479–92, DOI:10.1517/14728214.12.3.479.
  4. ^ Haskó G, Pacher P, A2A receptors in inflammation and injury: lessons learned from transgenic animals, in Journal of Leukocyte Biology, vol. 83, n. 3, March 2008, pp. 447–55, DOI:10.1189/jlb.0607359.
  5. ^ Kalda A, Yu L, Oztas E, Chen JF, Novel neuroprotection by caffeine and adenosine A(2A) receptor antagonists in animal models of Parkinson's disease, in Journal of the Neurological Sciences, vol. 248, n. 1-2, October 2006, pp. 9–15, DOI:10.1016/j.jns.2006.05.003.
  6. ^ Fuxe K, Ferré S, Genedani S, Franco R, Agnati LF, Adenosine receptor-dopamine receptor interactions in the basal ganglia and their relevance for brain function, in Physiology & Behavior, vol. 92, n. 1-2, September 2007, pp. 210–7, DOI:10.1016/j.physbeh.2007.05.034.
  7. ^ Schiffmann SN, Fisone G, Moresco R, Cunha RA, Ferré S, Adenosine A2A receptors and basal ganglia physiology, in Progress in Neurobiology, vol. 83, n. 5, December 2007, pp. 277–92, DOI:10.1016/j.pneurobio.2007.05.001.
  8. ^ Cunha RA, Ferré S, Vaugeois JM, Chen JF, Potential therapeutic interest of adenosine A2A receptors in psychiatric disorders, in Current Pharmaceutical Design, vol. 14, n. 15, 2008, pp. 1512–24, DOI:10.2174/138161208784480090.
  9. ^ Peart JN, Headrick JP, Adenosinergic cardioprotection: multiple receptors, multiple pathways, in Pharmacology & Therapeutics, vol. 114, n. 2, May 2007, pp. 208–21, DOI:10.1016/j.pharmthera.2007.02.004.
  10. ^ Cohen MV, Downey JM, Adenosine: trigger and mediator of cardioprotection, in Basic Research in Cardiology, vol. 103, n. 3, May 2008, pp. 203–15, DOI:10.1007/s00395-007-0687-7.
  11. ^ Ferré S, An update on the mechanisms of the psychostimulant effects of caffeine, in Journal of Neurochemistry, vol. 105, n. 4, May 2008, pp. 1067–79, DOI:10.1111/j.1471-4159.2007.05196.x.
  12. ^ Osadchii OE, Myocardial phosphodiesterases and regulation of cardiac contractility in health and cardiac disease, in Cardiovascular Drugs and Therapy / Sponsored by the International Society of Cardiovascular Pharmacotherapy, vol. 21, n. 3, June 2007, pp. 171–94, DOI:10.1007/s10557-007-6014-6.
  13. ^ Baraldi PG, Tabrizi MA, Gessi S, Borea PA, Adenosine receptor antagonists: translating medicinal chemistry and pharmacology into clinical utility, in Chemical Reviews, vol. 108, n. 1, January 2008, pp. 238–63, DOI:10.1021/cr0682195.
  14. ^ Cristalli G, Lambertucci C, Marucci G, Volpini R, Dal Ben D, A2A adenosine receptor and its modulators: overview on a druggable GPCR and on structure-activity relationship analysis and binding requirements of agonists and antagonists, in Current Pharmaceutical Design, vol. 14, n. 15, 2008, pp. 1525–52, DOI:10.2174/138161208784480081.
  15. ^ Unless else specified in boxes, then ref is:senselab
  16. ^ Entrez Gene: ADORA2A adenosine A2A receptor, su ncbi.nlm.nih.gov.
  17. ^ a b Jacobson KA, Gao ZG, Adenosine receptors as therapeutic targets, in Nature reviews. Drug discovery, vol. 5, n. 3, 2006, pp. 247–64, DOI:10.1038/nrd1983.

External links

Template:G protein-coupled receptors [[en:

Estratto da "https://it.wikipedia.org/w/index.php?title=Recettori_per_l%27adenosina&oldid=27865562"