title: Synthesis and structure-activity relationships of a novel series of tricyclic dihydropyridine-based KATP openers that potently inhibit bladder contractions in vitro.
abstract: Structure-activity relationships were investigated on a novel series of tricyclic dihydropyridine-containing K(ATP) openers. This diverse group of analogues, comprising a variety of heterocyclic rings fused to the dihydropyridine nucleus, was designed to determine the influence on activity of hydrogen-bond-donating and -accepting groups and their stereochemical disposition. Compounds were evaluated for K(ATP) activity in guinea pig bladder cells using a fluorescence-based membrane potential assay and in a pig bladder strip assay. The inhibition of spontaneous bladder contractions in vitro was also examined for a subset of compounds. All compounds studied showed greater potency to inhibit spontaneous bladder contractions relative to their potencies to inhibit contractions elicited by electrical stimulation.
authors.affiliation: Neuroscience Research, R4PM, AP10, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-6101, USA. william.a.carroll@abbott.com
authors.forename: William A
authors.initials: WA
authors.lastname: Carroll
authors.forename: Konstantinos A
authors.initials: KA
authors.lastname: Agrios
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Altenbach
authors.forename: Steven A
authors.initials: SA
authors.lastname: Buckner
authors.forename: Yiyuan
authors.initials: Y
authors.lastname: Chen
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Coghlan
authors.forename: Anthony V
authors.initials: AV
authors.lastname: Daza
authors.forename: Irene
authors.initials: I
authors.lastname: Drizin
authors.forename: Murali
authors.initials: M
authors.lastname: Gopalakrishnan
authors.forename: Rodger F
authors.initials: RF
authors.lastname: Henry
authors.forename: Michael E
authors.initials: ME
authors.lastname: Kort
authors.forename: Philip R
authors.initials: PR
authors.lastname: Kym
authors.forename: Ivan
authors.initials: I
authors.lastname: Milicic
authors.forename: Jamie C
authors.initials: JC
authors.lastname: Smith
authors.forename: Rui
authors.initials: R
authors.lastname: Tang
authors.forename: Sean C
authors.initials: SC
authors.lastname: Turner
authors.forename: Kristi L
authors.initials: KL
authors.lastname: Whiteaker
authors.forename: Henry
authors.initials: H
authors.lastname: Zhang
authors.forename: James P
authors.initials: JP
authors.lastname: Sullivan
mesh_terms: D000255:Adenosine Triphosphate / Q000502:physiology*; D000818:Animals; D004095:Dihydropyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004558:Electric Stimulation; D006168:Guinea Pigs; D006439:Hemodynamics / Q000187:drug effects; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006860:Hydrogen Bonding; D066298:In Vitro Techniques; D008564:Membrane Potentials; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D015221:Potassium Channels / Q000187:drug effects*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013552:Swine; D001743:Urinary Bladder / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D014563:Urodynamics / Q000187:drug effects
chemical_list: D004095:Dihydropyridines; D006575:Heterocyclic Compounds, 3-Ring; D015221:Potassium Channels; D000255:Adenosine Triphosphate