title: An investigation of the uroselective properties of four novel alpha(1a)-adrenergic receptor subtype-selective antagonists.
abstract: The development of alpha(1a)-adrenergic receptor (AR) subtype-selective antagonists is likely to result in uroselective agents that effectively treat benign prostatic hyperplasia (BPH) symptoms without causing undesirable side effects that may be due to vascular alpha(1)-AR blockade. The properties of four aryl piperazine compounds (RWJ-38063, RWJ-68141, RWJ-68157, and RWJ-69736) are described in this report and compared with the properties of tamsulosin, an alpha(1)-AR antagonist that is used in the treatment of BPH. Radioligand binding studies show that all four RWJ compounds have significantly higher affinity for the alpha(1a)-AR subtype than for the alpha(1b) or alpha(1d) subtype and display a higher level of receptor subtype selectivity than tamsulosin. The RWJ compounds were more potent in inhibiting (+/-)-norepinephrine-induced contractions of isolated rat prostate tissue than those of isolated rat aorta tissue, whereas tamsulosin had the reversed tissue selectivity. RWJ-38063 and RWJ-69736 had the highest potency in the isolated prostate tissue assays of the four RWJ compounds, with pK(B) values of 8.24 and 9.26, respectively, and were 319- and 100-fold more potent in their effects on isolated prostate tissue than aorta tissue. The in vivo uroselectivities of RWJ-38063, RWJ-69736, and tamsulosin were examined in anesthetized dogs. Both RWJ compounds suppressed the intraurethral pressure response to phenylephrine to a greater extent than the mean arterial pressure response; however, RWJ-69736 also caused a marked transient rise in heart rate. Although less potent, RWJ-38063 and RWJ-69736 were notably more uroselective than tamsulosin in this canine model.
authors.affiliation: The R. W. Johnson Pharmaceutical Research Institute, Drug Discovery Division, Raritan, New Jersey 08869-0602, USA. vpulito@prius.jnj.com
authors.forename: V L
authors.initials: VL
authors.lastname: Pulito
authors.forename: X
authors.initials: X
authors.lastname: Li
authors.forename: S S
authors.initials: SS
authors.lastname: Varga
authors.forename: L S
authors.initials: LS
authors.lastname: Mulcahy
authors.forename: K S
authors.initials: KS
authors.lastname: Clark
authors.forename: S A
authors.initials: SA
authors.lastname: Halbert
authors.forename: A B
authors.initials: AB
authors.lastname: Reitz
authors.forename: W V
authors.initials: WV
authors.lastname: Murray
authors.forename: L K
authors.initials: LK
authors.lastname: Jolliffe
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects; D019556:COS Cells; D004285:Dogs; D008297:Male; D010656:Phenylephrine / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D011467:Prostate / Q000187:drug effects / Q000502:physiology; D011728:Pyridones / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000494:pharmacology*; D051381:Rats; D020318:Rats, Long-Evans; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D014521:Urethra / Q000187:drug effects* / Q000502:physiology
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D010879:Piperazines; D010880:Piperidines; D011728:Pyridones; D011760:Pyrrolidinones; C410965:RWJ 38063; C410964:RWJ 68141; C410963:RWJ 68157; C410962:RWJ 69736; D018340:Receptors, Adrenergic, alpha-1; D010656:Phenylephrine