title: In vitro alpha1-adrenoceptor pharmacology of Ro 70-0004 and RS-100329, novel alpha1A-adrenoceptor selective antagonists.
abstract: It has been hypothesized that in patients with benign prostatic hyperplasia, selective antagonism of the alpha1A-adrenoceptor-mediated contraction of lower urinary tract tissues may, via a selective relief of outlet obstruction, lead to an improvement in symptoms. The present study describes the alpha1-adrenoceptor (alpha1-AR) subtype selectivities of two novel alpha1-AR antagonists, Ro 70-0004 (aka RS-100975) and a structurally-related compound RS-100329, and compares them with those of prazosin and tamsulosin. Radioligand binding and second-messenger studies in intact CHO-K1 cells expressing human cloned alpha1A-, alpha1B- and alpha1D-AR showed nanomolar affinity and significant alpha1A-AR subtype selectivity for both Ro 70-0004 (pKi 8.9: 60 and 50 fold selectivity) and RS-100329 (pKi 9.6: 126 and 50 fold selectivity) over the alpha1B- and alpha1D-AR subtypes respectively. In contrast, prazosin and tamsulosin showed little subtype selectivity. Noradrenaline-induced contractions of human lower urinary tract (LUT) tissues or rabbit bladder neck were competitively antagonized by Ro 70-0004 (pA2 8.8 and 8.9), RS-100329 (pA2 9.2 and 9.2), tamsulosin (pA2 10.4 and 9.8) and prazosin (pA2 8.7 and 8.3 respectively). Affinity estimates for tamsulosin and prazosin in antagonizing alpha1-AR-mediated contractions of human renal artery (HRA) and rat aorta (RA) were similar to those observed in LUT tissues, whereas Ro 70-0004 and RS-100329 were approximately 100 fold less potent (pA2 values of 6.8/6.8 and 7.3/7.9 in HRA/RA respectively). The alpha1A-AR subtype selectivity of Ro 70-0004 and RS-100329, demonstrated in both cloned and native systems, should allow for an evaluation of the clinical utility of a 'uroselective' agent for the treatment of symptoms associated with benign prostatic hyperplasia.
authors.affiliation: New Leads Discovery, Center for Biological Research, Neurobiology Unit, Roche Bioscience, Palo Alto, California 94304, USA. tim.williams@roche.com
authors.forename: T J
authors.initials: TJ
authors.lastname: Williams
authors.forename: D R
authors.initials: DR
authors.lastname: Blue
authors.forename: D V
authors.initials: DV
authors.lastname: Daniels
authors.forename: B
authors.initials: B
authors.lastname: Davis
authors.forename: T
authors.initials: T
authors.lastname: Elworthy
authors.forename: J R
authors.initials: JR
authors.lastname: Gever
authors.forename: M S
authors.initials: MS
authors.lastname: Kava
authors.forename: D
authors.initials: D
authors.lastname: Morgans
authors.forename: F
authors.initials: F
authors.lastname: Padilla
authors.forename: S
authors.initials: S
authors.lastname: Tassa
authors.forename: R L
authors.initials: RL
authors.lastname: Vimont
authors.forename: C R
authors.initials: CR
authors.lastname: Chapple
authors.forename: R
authors.initials: R
authors.lastname: Chess-Williams
authors.forename: R M
authors.initials: RM
authors.lastname: Eglen
authors.forename: D E
authors.initials: DE
authors.lastname: Clarke
authors.forename: A P
authors.initials: AP
authors.lastname: Ford
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D003001:Cloning, Molecular; D006224:Cricetinae; D006801:Humans; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000494:pharmacology; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009638:Norepinephrine / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D011224:Prazosin / Q000494:pharmacology; D011817:Rabbits; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1; D013449:Sulfonamides / Q000494:pharmacology; D000077409:Tamsulosin; D013941:Thymine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014551:Urinary Tract / Q000378:metabolism
chemical_list: C547713:ADRA1A protein, human; C547715:Adra1a protein, rat; D058668:Adrenergic alpha-1 Receptor Antagonists; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D007295:Inositol Phosphates; D010879:Piperazines; C120711:RS 100329; D018340:Receptors, Adrenergic, alpha-1; D013449:Sulfonamides; C120710:Ro 70-0004; D000077409:Tamsulosin; D013941:Thymine; D009638:Norepinephrine; D011224:Prazosin