Purinoceptors as therapeutic targets for lower urinary tract dysfunction.
Lower urinary tract symptoms (LUTS) are present in many common urological syndromes. However, their current suboptimal management by muscarinic and alpha(1)-adrenoceptor antagonists leaves a significant opportunity for the discovery and development of superior medicines. As potential targets for such therapeutics, purinoceptors have emerged over the last two decades from investigations that have established a prominent role for ATP in the regulation of urinary bladder function under normal and pathophysiological conditions. In particular, evidence suggests that ATP signaling via P2X(1) receptors participates in the efferent control of detrusor smooth muscle excitability, and that this function may be heightened in disease and aging. ATP also appears to be involved in bladder sensation, via activation of P2X(3) and P2X(2/3) receptors on sensory afferent neurons, both within the bladder itself and possibly at central synapses. Such findings are based on results from classical pharmacological and localization studies in non-human and human tissues, knockout mice, and studies using recently identified pharmacological antagonists--some of which possess attributes that offer the potential for optimization into candidate drug molecules. Based on recent advances in this field, it is clearly possible that the development of selective antagonists for these receptors will occur that could lead to therapies offering better relief of sensory and motor symptoms for patients, while minimizing the systemic side effects that limit current medicines.
Ford
Anthony P D W
AP
Department of Biochemical Pharmacology, Roche Palo Alto, CA 94304, USA.
Gever
Joel R
JR
Nunn
Philip A
PA
Zhong
Yu
Y
Cefalu
Joseph S
JS
Dillon
Michael P
MP
Cockayne
Debra A
DA
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D015195:Drug Design; D006801:Humans; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000294:innervation / Q000378:metabolism; D009475:Neurons, Afferent / Q000378:metabolism; D009476:Neurons, Efferent / Q000378:metabolism; D010636:Phenols / Q000494:pharmacology / Q000627:therapeutic use; D011083:Polycyclic Compounds / Q000494:pharmacology / Q000627:therapeutic use; D058914:Purinergic Antagonists; D011743:Pyrimidines / Q000494:pharmacology; D011983:Receptors, Purinergic / Q000378:metabolism*; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D058469:Receptors, Purinergic P2X; D058476:Receptors, Purinergic P2X2; D058477:Receptors, Purinergic P2X3; D001743:Urinary Bladder / Q000294:innervation / Q000378:metabolism*; D001745:Urinary Bladder Diseases / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D014554:Urination
C470346:A-317491; C546401:P2RX2 protein, human; C546407:P2RX3 protein, human; C546402:P2rx2 protein, mouse; C546409:P2rx3 protein, mouse; D010636:Phenols; D011083:Polycyclic Compounds; D058914:Purinergic Antagonists; D011743:Pyrimidines; D011983:Receptors, Purinergic; D018048:Receptors, Purinergic P2; D058469:Receptors, Purinergic P2X; D058476:Receptors, Purinergic P2X2; D058477:Receptors, Purinergic P2X3; D000255:Adenosine Triphosphate