title: RBx 6198: a novel alpha1-adrenoceptor antagonist for the treatment of benign prostatic hyperplasia.
abstract: The present study, investigates the effect of RBx 6198, 2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-1-yl]-propyl}-3a, 4, 7, 7a-tetrahydro-isoindole-1, 3,-dione, a novel alpha(1)-adrenoceptor antagonist, in both in vitro and in vivo test systems. RBx 6198 is a potent (nanomolar affinity) alpha(1A)-adrenoceptor antagonist with demonstrable uroselectivity in anaesthesized dog model. In radioligand binding studies using human recombinant receptors, RBx 6198 exhibited high selectivity (approximately 50 fold) for the alpha(1A)-adrenoceptor subtype as compared to alpha(1B)-adrenoceptor subtype. In order to assess tissue selectivity, the antagonistic effect of RBx 6198 on the phenylephrine induced contractile response of isolated rat prostate, spleen and aorta was characterized. RBx 6198 was 8 fold more potent in inhibiting phenylephrine-evoked contractions of isolated tissues compared to tamsulosin. However, the compound was non-selective for alpha(1A) vs. alpha(1D)-adrenoceptor like tamsulosin. In anaesthetized beagle dogs RBx 6198 suppressed the intraurethral pressure response to phenylephrine to a greater extent than the mean arterial pressure response thereby demonstrating uroselectivity consistent with in vitro binding and functional data. RBx 6198 was 6.4 fold more uroselective as compared to tamsulosin after i.v. route dose administration. Taken together all results from preclinical studies, it is suggested that RBx 6198 is a novel alpha(1)-adrenoceptor antagonist that exhibited improved pharmacological profile over tamsulosin in both in vitro and in vivo.
authors.affiliation: Department of Pharmacology, Ranbaxy Research Laboratories, Plot -20, Sector-18, Gurgaon, 122015, India. kamna.nanda@ranbaxy.com
authors.forename: Kamna
authors.initials: K
authors.lastname: Nanda
authors.forename: Krishna S
authors.initials: KS
authors.lastname: Naruganahalli
authors.forename: Suman
authors.initials: S
authors.lastname: Gupta
authors.forename: Shivani
authors.initials: S
authors.lastname: Malhotra
authors.forename: Atul
authors.initials: A
authors.lastname: Tiwari
authors.forename: Laxminarayan G
authors.initials: LG
authors.lastname: Hegde
authors.forename: Sanjay
authors.initials: S
authors.lastname: Jain
authors.forename: Neelima
authors.initials: N
authors.lastname: Sinha
authors.forename: Jung B
authors.initials: JB
authors.lastname: Gupta
authors.forename: Anita
authors.initials: A
authors.lastname: Chugh
authors.forename: Nitya
authors.initials: N
authors.lastname: Anand
authors.forename: Abhijit
authors.initials: A
authors.lastname: Ray
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004285:Dogs; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D010656:Phenylephrine; D010797:Phthalimides / Q000008:administration & dosage / Q000494:pharmacology*; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D011467:Prostate / Q000187:drug effects / Q000378:metabolism; D011470:Prostatic Hyperplasia / Q000188:drug therapy* / Q000503:physiopathology; D011485:Protein Binding; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D000077409:Tamsulosin
chemical_list: C541785:2-(3-(4-(2-isopropoxyphenyl)piperazin-1-yl)propyl)-3a,4,7,7a-tetrahydroisoindole-1,3-dione; D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D010797:Phthalimides; D010879:Piperazines; D013449:Sulfonamides; D010656:Phenylephrine; D000077409:Tamsulosin