title: Pharmacological properties of TD-6301, a novel bladder selective muscarinic receptor antagonist.
abstract: Existing antimuscarinic drugs for overactive bladder have high affinity for M(3)/M(1) muscarinic receptors and consequently produce M(3)/M(1)-mediated adverse effects including dry mouth, constipation, mydriasis and somnolence. TD-6301 is a M(2/4) muscarinic receptor-selective antagonist developed for the treatment of overactive bladder. The present studies characterize the in vitro and in vivo pharmacological properties of this molecule in comparison to other marketed antimuscarinics agents. In radioligand binding studies, TD-6301 was found to possess high affinity for human M(2) muscarinic receptor (K(i)=0.36 nM) and was 31, 36, 2 and 128-fold selective for the human M(2) muscarinic receptor compared to the M(1), M(3), M(4) and M(5) muscarinic receptors, respectively. The in vivo bladder selectivity of TD-6301 in rats was determined to be 26, 28, >100, 16 and 0.4-fold, respectively, assessed by comparing its potency for inhibition of volume-induced bladder contractions to that for inhibition of oxotremorine-induced salivation, inhibition of small-intestinal transit, decreases in locomotor activity, increases in pupil diameter and increases in heart rate. TD-6301 was more potent in inhibiting volume-induced bladder contractions (ID(50)=0.075 mg/kg) compared to oxotremorine-induced salivation (ID(50)=1.0 mg/kg) resulting in a bladder/salivary gland selectivity ratio greater than that observed for tolterodine, oxybutynin, darifenacin and solifenacin. The preclinical properties of TD-6301 suggest that this molecule is likely to be efficacious in overactive bladder patients with a lower propensity to cause M(3) muscarinic receptor mediated adverse effects.
authors.affiliation: Theravance, Inc, South San Francisco, California 94080, USA. amcnamara@theravance.com
authors.forename: Alexander
authors.initials: A
authors.lastname: McNamara
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Pulido-Rios
authors.forename: Shelley
authors.initials: S
authors.lastname: Sweazey
authors.forename: Glenmar P
authors.initials: GP
authors.lastname: Obedencio
authors.forename: Harold
authors.initials: H
authors.lastname: Thibodeaux
authors.forename: Travis
authors.initials: T
authors.lastname: Renner
authors.forename: Scott R
authors.initials: SR
authors.lastname: Armstrong
authors.forename: Tod
authors.initials: T
authors.lastname: Steinfeld
authors.forename: Adam D
authors.initials: AD
authors.lastname: Hughes
authors.forename: Richard D
authors.initials: RD
authors.lastname: Wilson
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Jasper
authors.forename: Mathai
authors.initials: M
authors.lastname: Mammen
authors.forename: Sharath S
authors.initials: SS
authors.lastname: Hegde
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D009119:Muscle Contraction / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D043585:Receptor, Muscarinic M2 / Q000037:antagonists & inhibitors*; D043588:Receptor, Muscarinic M4 / Q000037:antagonists & inhibitors*; D012469:Salivary Glands / Q000187:drug effects / Q000378:metabolism; D012472:Salivation / Q000187:drug effects; D001743:Urinary Bladder / Q000187:drug effects / Q000378:metabolism; D053201:Urinary Bladder, Overactive / Q000188:drug therapy
chemical_list: C541080:1-(4-methoxypyridin-3-ylmethyl)-4-((N-(7-(3-(S)-1-carbamoyl-1,1-diphenylmethyl)pyrrolidin-1-yl)hept-1-yl)-N-(isopropyl)amino)piperidine; D018727:Muscarinic Antagonists; D010880:Piperidines; D011725:Pyridines; D043585:Receptor, Muscarinic M2; D043588:Receptor, Muscarinic M4