Potassium channel subtypes as molecular targets for overactive bladder and other urological disorders.
Potassium channels have re-emerged as attractive targets for overactive bladder and other urological diseases in recent years, in part due to an enhanced understanding of their molecular heterogeneity, tissue distribution, functional roles and regulation in physiological and pathological states. Cloning and heterologous expression analysis, coupled with the advancement of improved high-throughput screening techniques, have enabled expeditious identification of selective small-molecule openers and blockers for ATP-sensitive K+ channels, Ca2+-activated K+ channels and voltage-dependent K+ channel-KQT-like subfamily (KCNQ) members, and has paved the way in the assessment of efficacy and adverse effects in preclinical models. This review focuses on the rationale for molecular targeting of K+ channels, the current status of target validation, including preclinical proof-of-concept studies, and provides perspectives on the limitations and hurdles to be overcome in realising the potential of these targets for diverse urological indications such as overactive bladder, erectile dysfunction and prostate diseases.
Abbott Laboratories, Neuroscience Research, Global Pharmaceutical Research and Development, Building AP9A, 3rd floor, 100 Abbott Park Road, Abbott Park, Illinois 60064, USA. murali.gopalakrishnan@abbott.com
Murali
M
Gopalakrishnan
Char-Chang
CC
Shieh
D000368:Aged; D000818:Animals; D002118:Calcium / Q000378:metabolism; D004311:Double-Blind Method; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D007172:Erectile Dysfunction / Q000188:drug therapy / Q000503:physiopathology; D005260:Female; D000882:Haplorhini; D006801:Humans; D017136:Ion Transport / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D015394:Molecular Structure; D010410:Penile Erection / Q000502:physiology; D011188:Potassium / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use; D015221:Potassium Channels / Q000145:classification / Q000187:drug effects* / Q000502:physiology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000503:physiopathology; D016032:Randomized Controlled Trials as Topic; D051381:Rats; D013268:Stimulation, Chemical; D013552:Swine; D001745:Urinary Bladder Diseases / Q000188:drug therapy* / Q000503:physiopathology; D001750:Urinary Bladder, Neurogenic / Q000188:drug therapy / Q000503:physiopathology; D014554:Urination / Q000502:physiology; D014555:Urination Disorders / Q000188:drug therapy / Q000503:physiopathology
D026902:Potassium Channel Blockers; D015221:Potassium Channels; D011188:Potassium; D002118:Calcium