title: Discovery of LASSBio-772, a 1,3-benzodioxole N-phenylpiperazine derivative with potent alpha 1A/D-adrenergic receptor blocking properties.
abstract: We described herein the discovery of 1-(2-(benzo[d] [1,3]dioxol-6-yl)ethyl)-4-(2-methoxyphenyl) piperazine (LASSBio-772), as a novel potent and selective alpha 1A/1D adrenoceptor (AR) antagonist selected after screening of functionalized N-phenylpiperazine derivatives in phenylephrine-induced vasoconstriction of rabbit aorta rings. The affinity of LASSBio-772 for alpha 1A and alpha 1B AR subtypes was determined through displacement of [(3)H]prazosin binding. We obtained Ki values of 0.14 nM for the alpha 1A-AR, similar to that displayed by tamsulosin (K(i) = 0.13 nM) and 5.55 nM for the alpha 1B-AR, representing a 40-fold higher affinity for alpha 1A-AR. LASSBio-772 also presented high affinity (K(B) = 0.025 nM) for the alpha 1D-AR subtype in the functional rat aorta assay, showing to be equipotent to tamsulosin (K(B) = 0.017 nM).
authors.affiliation: Laboratório de Avaliação e Síntese de Substâncias Bioativas(1) (LASSBio), Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, PO Box 68.023, 21941-902 Rio de Janeiro, RJ, Brazil.
authors.forename: Luiz A S
authors.initials: LA
authors.lastname: Romeiro
authors.forename: Marcos
authors.initials: M
authors.lastname: da Silva Ferreira
authors.forename: Leandro L
authors.initials: LL
authors.lastname: da Silva
authors.forename: Helena C
authors.initials: HC
authors.lastname: Castro
authors.forename: Ana L P
authors.initials: AL
authors.lastname: Miranda
authors.forename: Cláudia L M
authors.initials: CL
authors.lastname: Silva
authors.forename: François
authors.initials: F
authors.lastname: Noël
authors.forename: Jéssica B
authors.initials: JB
authors.lastname: Nascimento
authors.forename: Claudia V
authors.initials: CV
authors.lastname: Araújo
authors.forename: Eduardo
authors.initials: E
authors.lastname: Tibiriçá
authors.forename: Eliezer J
authors.initials: EJ
authors.lastname: Barreiro
authors.forename: Carlos A M
authors.initials: CA
authors.lastname: Fraga
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects*; D052117:Benzodioxoles / Q000138:chemical synthesis* / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism; D022781:Hepatocytes / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D010656:Phenylephrine / Q000494:pharmacology; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology; D011224:Prazosin / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000737:chemistry / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D000077409:Tamsulosin; D046509:Tissue Culture Techniques; D014316:Tritium; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: C000598115:1-(2-(benzo(d)(1,3)dioxol-6-yl)ethyl)-4-(2-methoxyphenyl)piperazine; D058668:Adrenergic alpha-1 Receptor Antagonists; D052117:Benzodioxoles; D010879:Piperazines; D020033:Protein Isoforms; D018340:Receptors, Adrenergic, alpha-1; D013449:Sulfonamides; D014316:Tritium; D010656:Phenylephrine; D000077409:Tamsulosin; D011224:Prazosin