title: Synthesis of and radioligand binding studies with a tritiated pinacidil analogue: receptor interactions of structurally different classes of potassium channel openers and blockers.
abstract: The synthesis of N-cyano-N'-[1,1-dimethyl-[2,2,3,3-3H]propyl]-N"-(3- pyridinyl)guanidine, [3H]-15, is described. The utility of this tritiated radioligand in characterizing the interactions of potassium channel openers and blockers with their receptors is demonstrated. Potassium channel openers of the pinacidil, cromakalim, aprikalim, diazoxide, and minoxidil types, as well as KATP channel blockers of the glibenclamide and eosine types, are all capable of displacing [3H]-15 from its receptor. The results indicate that all of these compounds interact with the same target protein, but that several different allosterically coupled receptor binding sites are probably involved. The highly significant correlation between the ability of the structurally diverse potassium channel openers to inhibit [3H]-15 binding and to relax vascular smooth muscle is consistent with their receptor binding sites being closely associated with the potassium channel protein which is the functional target of this class of drugs.
authors.affiliation: Preclinical Research Department, Sandoz Pharma Ltd., Basel, Switzerland.
authors.forename: P W
authors.initials: PW
authors.lastname: Manley
authors.forename: U
authors.initials: U
authors.lastname: Quast
authors.forename: H
authors.initials: H
authors.lastname: Andres
authors.forename: K
authors.initials: K
authors.lastname: Bray
mesh_terms: D000818:Animals; D001665:Binding Sites; D004347:Drug Interactions; D006146:Guanidines / Q000138:chemical synthesis* / Q000378:metabolism* / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D020110:Pinacidil; D015221:Potassium Channels / Q000187:drug effects*; D011725:Pyridines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D014665:Vasodilator Agents / Q000138:chemical synthesis*
chemical_list: D006146:Guanidines; D015221:Potassium Channels; D011725:Pyridines; D014665:Vasodilator Agents; C073896:N-cyano-N'-(1,1-dimethylpropyl)-N''-(3-pyridinyl)guanidine; D020110:Pinacidil