title: Structure-activity studies of potassium channel opening in pinacidil-type cyanoguanidines, nitroethenediamines, thioureas, and ureas.
abstract: Potassium channel opening activity for pinacidil-type cyanoguanidines, nitroethenediamines, thioureas, and ureas, has been assessed through simultaneous measurement of spontaneous contractile activity and stimulation of 86Rb+ efflux from rat portal veins loaded with 86Rb+. The good correlation between these two effects suggests that the vasodilator activity of the compounds is directly attributable to an increased opening of potassium channels. The resulting quantitative in vitro data has been used to analyze the structure-activity relationships for potassium channel opening, allowing the biological activity to be rationalized in terms of a pharmacophore involving a hydrogen-bond-acceptor element, a hydrogen-bond-donor element, and a lipophilic binding group. A model for the binding of pinacidil-related compounds to their potassium channel receptor has been developed, and compounds designed to test this model have been synthesized and tested. Prototropic equilibria are implicated as playing a fundamental role in determining the hydrogen-bonding ability of the compounds, and conformational changes in the receptor are invoked to explain disparities in the chiral recognition of lipophilic groups in different compounds.
authors.affiliation: Preclinical Research, Sandoz Pharma Ltd., Basel, Switzerland.
authors.forename: P W
authors.initials: PW
authors.lastname: Manley
authors.forename: U
authors.initials: U
authors.lastname: Quast
mesh_terms: D000818:Animals; D003959:Diamines / Q000737:chemistry / Q000494:pharmacology*; D006146:Guanidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015640:Ion Channel Gating / Q000187:drug effects*; D008297:Male; D008968:Molecular Conformation; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects; D020110:Pinacidil; D011169:Portal Vein / Q000187:drug effects / Q000502:physiology; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D011919:Rats, Inbred Strains; D012414:Rubidium Radioisotopes / Q000378:metabolism; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000737:chemistry / Q000494:pharmacology*; D014508:Urea / Q000737:chemistry / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D003959:Diamines; D006146:Guanidines; D015221:Potassium Channels; D012414:Rubidium Radioisotopes; D014665:Vasodilator Agents; D020110:Pinacidil; D014508:Urea; D013890:Thiourea