Adenosine Ai receptor antagonist

Adenosine has been proposed to induce sleep by inhibiting cholinergic neurons of the BFB and the brainstem. In this respect, adenosine and the adenosine transport inhibitor NBTI decrease the discharge rate of BFB neurons during W, whereas the adenosine Ai receptor antagonist CPDX induces the opposite effects (Alam et al., 1999 Strecker et al., 2000). In addition, perfusion of adenosine into... 

Table 8 Thiazole and thiadiazole analogues in modeling the adenosine Ai receptor antagonistic activity (Fig. 9) [105] ...

With the CODESSA descriptors, Borghini et al. [105] also carried out a QSAR study on the adenosine Ai receptor antagonistic activity of another series of thiazoles/thiadiazoles (Fig. 9) [93,94]. In this, 27 compounds were included for training the model and seven compounds were used for testing the model (Fig. 9, Table 8). The following three descriptor model in terms of MPCN (minimum partial charge on the N atom), ZXS/ZXR (ZX Shadow/ZX Rectangle), and PP/D (polarity parameter/square distance) has been derived to explain the affinity of these compounds to the adenosine Al receptor. 

In a series of adenosine Ai receptor antagonists," simple homologation of the carbon chain bearing the carboxylic group improved the bioavailability, the selectivity and the water solubility (Figure 38.3). 

Dalpiaz A, Townsend-Nicholson A, Beukers MW, Schofield P, Ijzerman AP. Thermodynamics of full agonist, partial agonist and antagonist binding to wild type and mutant adenosine Ai receptors. Biochem Pharmacol 1998 56 1437-1445. 

Adenosine is produced by many tissues, mainly as a byproduct of ATP breakdown. It is released from neurons, glia and other cells, possibly through the operation of the membrane transport system. Its rate of production varies with the functional state of the tissue and it may play a role as an autocrine or paracrine mediator (e.g. controlling blood flow). The uptake of adenosine is blocked by dipyridamole, which has vasodilatory effects. The effects of adenosine are mediated by a group of G protein-coupled receptors (the Gi/o-coupled Ai- and A3 receptors, and the Gs-coupled A2a-/A2B receptors). Ai receptors can mediate vasoconstriction, block of cardiac atrioventricular conduction and reduction of force of contraction, bronchoconstriction, and inhibition of neurotransmitter release. A2 receptors mediate vasodilatation and are involved in the stimulation of nociceptive afferent neurons. A3 receptors mediate the release of mediators from mast cells. Methylxanthines (e.g. caffeine) function as antagonists of Ai and A2 receptors. Adenosine itself is used to terminate supraventricular tachycardia by intravenous bolus injection. 

Presently, only adenosine itself is approved for clinical use. It is used widely in the treatment of supraventricular tachycardia and in cardiac stress imaging to assess coronary artery disease [5]. Other agonists and antagonists and an allosteric modulator of the Ai receptor are in clinical trials for a variety of indications. 

O Kane EM, Stone TW (1998) Interaction between adenosine Ai and A2 receptor-mediated responses in the rat hippocampus in vitro. Eur J Pharmacol 362 17-25 Ohkubo S, Kimura J, Matsuoka I (2000) Ecto-alkaline phosphatase in NG108-15 cells a key enzyme mediating PI antagonist sensitive ATP response. Br J Pharmacol 131 1667-2 Okada M, Mizuno K, Kaneko S (1996) Adenosine Ai and A2 receptors modulate extracellular dopamine levels in rat striatum. Neurosci Lett 212 53-6 Okada M, Nutt DJ, Murakami T et al (2001) Adenosine receptor subtypes modulate two major functional pathways for hippocampal serotonin release. J Neurosci 21 628 40 Oliveira L, Correia-de-Sd P (2005) Protein kinase A and Cavl (L-Type) channels are common targets to facilitatory adenosine A2a and muscarinic Mj receptors on rat motoneurons. Neurosignals 14 262-72... 

Fig. 9 General structure of thiazole and thiadiazole class of adenosine Ai and A3 receptor antagonists and their quinazoline, isoquinoline seed structures...

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