Brown, Gerard Sean; (2001) Pharmacological agents that distinguish between P2X receptor subtypes. Doctoral thesis (Ph.D.), University College London.

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Abstract

The activity of novel pharmacological agents at recombinant P2X receptors was studied to find agents that distinguish between P2X receptor subtypes, particularly P2X1 and P2X3. Adenine nucleotide derivatives and diadenosine polyphosphates (ApnA, n = 2-6) were investigated as P2X receptor agonists. PAPET and HT-AMP were agonists, to varying degrees, at P2X1-4 receptors. PAPET displayed higher affinity but lower efficacy than ATP at P2X1 and P2X3 receptors. HT-AMP showed higher affinity than ATP at P2X3 receptors yet acted as a partial agonist at P2X1-4 receptors. Diadenosine polyphosphates also showed selectivity in their actions at P2X1-4 receptors. Ap2A was inactive and Ap3-6A showed varying affinities and efficacies as agonists at P2X1-4. Ap3A was most effective at distinguishing between P2X1 and P2X3 receptors with over 100 fold difference between their respective EC50 values A series of PPADS derivatives, involving chemical manipulation of the phenylazo moiety and/or the pyridoxal phosphate moiety, showed nanomolar activity at P2X1 and P2X3 receptors with variable degrees of selectivity between these receptor subtypes. The most potent compounds were studied in detail and shown to be nonsurmountable antagonists. A comparison of like data for recombinant P2X1 receptors and native P2X1-like receptors in vas deferens revealed a number of pharmacological anomalies. Co-expression of P2X1 and P2X2 revealed a novel pH-sensitive phenotype although this heteromeric receptor is unlikely to account for the difference between rP2X1 and the native P2X subtype(s) in this tissue. A step forward has been made in the search of pharmacological agents that distinguish between P2X1 and P2X3 receptors. Antagonist-resistant ATP responses in the vas deferens lend weight for other contraction-mediating P2 receptors in this preparation. Greater diversity of purinergic signalling was revealed through co-expression of P2X receptors and underlines the need for further novel pharmacological tools.

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