Synthesis and structure-activity relationships of a novel series of tricyclic dihydropyridine-based KATP openers that potently inhibit bladder contractions in vitro.
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.
Carroll
William A
WA
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
Agrios
Konstantinos A
KA
Altenbach
Robert J
RJ
Buckner
Steven A
SA
Chen
Yiyuan
Y
Coghlan
Michael J
MJ
Daza
Anthony V
AV
Drizin
Irene
I
Gopalakrishnan
Murali
M
Henry
Rodger F
RF
Kort
Michael E
ME
Kym
Philip R
PR
Milicic
Ivan
I
Smith
Jamie C
JC
Tang
Rui
R
Turner
Sean C
SC
Whiteaker
Kristi L
KL
Zhang
Henry
H
Sullivan
James P
JP
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
D004095:Dihydropyridines; D006575:Heterocyclic Compounds, 3-Ring; D015221:Potassium Channels; D000255:Adenosine Triphosphate