title: Inhibition by imidazoline and imidazolidine derivatives of glibenclamide-sensitive K+ currents in Xenopus oocytes.
abstract: The effects of imidazoline and imidazolidine derivatives on glibenclamide-sensitive K+ currents induced by the novel K+ channel opener, Y-26763 ((+)-(3S,4R)-4-(N-acetyl-N-benzyloxyamino)-6-cyano-3,4-dihydro-2,2 -dimethyl-2H-1-benzopyran-3-ol), were investigated in voltage-clamped follicle-enclosed Xenopus oocytes. Of 14 imidazoline derivatives and seven imidazolidine derivatives tested, phenotalmine, (-)-cibenzoline, (+)-cibenzoline, alinidine, oxymetazoline, antazoline, midaglizole, xylometazoline, tramazoline and ST91 (2-(2,6-diethylphenylamino)-2-imidazoline hydrochloride) potently suppressed Y-26763-induced K+ currents (IC50 < 80 microM). The compounds which lack an aromatic ring in their structure, 2-methyl-2-imidazole and 2-hydrazino-2-imidazoline, did not affect the K+ currents. Clonidine and idazoxan, which both bind to imidazoline-preferring binding sites with high affinity in various tissues, showed only a small inhibitory effect on Y-26763-induced K+ currents (IC50 780 microM and 955 microM, respectively). The non-imidazoline/non-imidazolidine alpha-adrenoceptor antagonists, WB-4101 (2-(2,6-dimethoxy-phenoxyethyl)-aminomethyl-1,4-benzodioxane hydrochloride), yohimbine and rauwolscine, showed suppressive effects on Y-26763-induced K+ currents (IC50 203 microM, 813 microM and 832 microM, respectively). Octopamine (1 mM), a non-imidazoline/non-imidazolidine alpha-adrenoceptor agonist, was inactive. The results suggest that (1) an aromatic ring or aromatic rings are an essential moiety for imidazoline or imidazolidine derivatives to block glibenclamide-sensitive K+ currents in oocytes, and (2) the K+ current-blocking ability of imidazolines and imidazolidines is related to the alkylation of the benzene ring and the existence of a tertiary amine structure. The K+ current-blocking effects of imidazolines or imidazolidines may not be mediated by alpha-adrenoceptors, at least in follicle-enclosed Xenopus oocytes.
authors.affiliation: Department of Pharmacology, National Defense Medical College, Saitama, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Sakuta
authors.forename: K
authors.initials: K
authors.lastname: Okamoto
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology; D001578:Benzopyrans / Q000037:antagonists & inhibitors / Q000494:pharmacology; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004594:Electrophysiology; D005260:Female; D005905:Glyburide / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects; D013329:Structure-Activity Relationship; D013453:Sulfonylurea Compounds / Q000494:pharmacology; D014982:Xenopus laevis
chemical_list: D000959:Antihypertensive Agents; D001578:Benzopyrans; D007004:Hypoglycemic Agents; D007093:Imidazoles; D015221:Potassium Channels; D011942:Receptors, Adrenergic, alpha; D013453:Sulfonylurea Compounds; C074338:Y 26763; D005905:Glyburide