title: Ex vivo and in vivo alpha1-adrenoceptor binding characteristics of a novel alpha1L-adrenoceptor antagonist, JTH-601, in rat tissues.
abstract: In vitro, ex vivo and in vivo alpha1-adrenoceptor binding of JTH-601 (3-[N-[2-(4-hydroxy-2-isopropyl-5-methylphenoxy)ethyl]-N-methylaminometh yl]-4-methoxy-2,5,6-trimethyl-phenol hemifumarate), a novel alpha1L-adrenoceptor antagonist, in rat tissues was investigated. JTH-601 competed in a concentration-dependent manner with [3H]prazosin for binding sites in the prostate, submaxillary gland and spleen of rats in vitro, and the inhibitory effect was not largely different among these tissues, as shown by the Ki values of 2-3 nM. At 0.25, 0.5 and 3 h after oral administration of JTH-601 (6.5 micromol/kg) in rats, there was a significant (57, 64 and 28%, respectively) increase in the apparent dissociation constant (Kd) for prostatic [3H]prazosin binding, compared to the control value. The administration of a higher dose (21.8 micromol/kg) of this agent produced greater (67-99%) increases in Kd values for prostatic [3H]prazosin binding at 0.5-12 h later. Similar significant increases in Kd values, as with the prostate, were seen in the submaxillary gland and heart 0.25-12 h after the oral administration of JTH-601 (6.5 and 21.8 micromol/kg), but significant increases in the spleen and cerebral cortex were seen only at 0.25-3 h and 0.5 h, respectively. At 10 min of i.v. injection of [3H]JTH-601 in rats, in vivo specific binding was observed in the prostate, cerebral cortex, submaxillary gland, spleen and heart but not in the aorta. The binding in the prostate, submaxillary gland and heart, but not in the cerebral cortex and spleen, lasted until 120 min. It is concluded that JTH-601 may exert a considerably sustained blockade of alpha1-adrenoceptors in the prostate of rats. This finding may be important in characterizing the therapeutic effect of JTH-601 for bladder outlet obstruction in patients with benign prostatic hyperplasia.
authors.affiliation: Department of Biopharmacy, School of Pharmaceutical Sciences, University of Shizuoka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Ohkura
authors.forename: S
authors.initials: S
authors.lastname: Yamada
authors.forename: A
authors.initials: A
authors.lastname: Tohma
authors.forename: R
authors.initials: R
authors.lastname: Kimura
authors.forename: K
authors.initials: K
authors.lastname: Aisaka
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive; D003408:Cresols / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D011467:Prostate / Q000187:drug effects* / Q000378:metabolism; D019275:Radiopharmaceuticals / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D014018:Tissue Distribution; D014316:Tritium
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D003408:Cresols; D019275:Radiopharmaceuticals; D018340:Receptors, Adrenergic, alpha-1; D014316:Tritium; C101291:JTH 601