title: Design and evaluation of nitrosylated alpha-adrenergic receptor antagonists as potential agents for the treatment of impotence.
abstract: We designed and evaluated a new class of molecules, nitrosylated alpha-adrenergic receptor antagonists, as potential agents for the treatment of impotence. In in vitro studies with human and rabbit corpus cavernosum strips in organ chambers, the alpha-adrenergic receptor antagonists (alpha-ARAs) moxisylyte and yohimbine and their corresponding nitrosylated compounds, SNO-moxisylyte (NMI-221) and SNO-yohimbine (NMI-187), concentration-dependently relaxed endothelin-induced contraction. The nitrosylated compounds were significantly more potent than the parent alpha-ARA. In human tissues, the specific phosphodiesterase type 5 inhibitor zaprinast potentiated the relaxing effects of the nitrosylated compounds. Only nitrosylated compounds induced accumulation of cyclic GMP in rabbit corpus cavernosum strips. Yohimbine and NMI-187 demonstrated a potent alpha2-blocking activity, with no significant differences in pA2 values (8.9 versus 8.2, respectively). Moxisylyte and NMI-221 showed moderate potency in antagonizing phenylephrine contraction, with comparable pA2 values for both molecules (6.5 versus 6.6, respectively). alpha-Adrenergic receptor-binding studies showed similar binding affinities for the alpha-ARA and their corresponding nitrosylated compounds. In vivo, intracavernosal injection of nitrosylated molecules caused greater increases in intracavernosal pressure (NMI-221 versus moxisylyte) that were more long lasting than those of moxisylyte or yohimbine. There were no significant differences between nitrosylated and non-nitrosylated compounds in the magnitude of systemic mean arterial pressure decrease after intracavernosal injection. alpha-ARA and the nitrosylated compounds showed no pain-inducing activity as evaluated with the paw-lick model in mice. In summary, nitrosylated alpha-ARA have the dual functionalities of nitric oxide donors and alpha-ARA. These drugs induced penile erection in animals, suggesting their possible therapeutic value as agents for the local pharmacological treatment of impotence.
authors.affiliation: Departamento de Investigación, Hospital Ramón y Cajal, Fundación para la Investigación y el Desarrollo en Andrología, Madrid, Spain. isaenz@ntserver.coronadoserv.com
authors.forename: I S
authors.initials: IS
authors.lastname: de Tejada
authors.forename: D S
authors.initials: DS
authors.lastname: Garvey
authors.forename: J D
authors.initials: JD
authors.lastname: Schroeder
authors.forename: T
authors.initials: T
authors.lastname: Shelekhin
authors.forename: L G
authors.initials: LG
authors.lastname: Letts
authors.forename: A
authors.initials: A
authors.lastname: Fernández
authors.forename: B
authors.initials: B
authors.lastname: Cuevas
authors.forename: S
authors.initials: S
authors.lastname: Gabancho
authors.forename: V
authors.initials: V
authors.lastname: Martínez
authors.forename: J
authors.initials: J
authors.lastname: Angulo
authors.forename: M
authors.initials: M
authors.lastname: Trocha
authors.forename: P
authors.initials: P
authors.lastname: Marek
authors.forename: P
authors.initials: P
authors.lastname: Cuevas
authors.forename: S W
authors.initials: SW
authors.lastname: Tam
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D006152:Cyclic GMP / Q000378:metabolism; D015195:Drug Design; D016232:Endothelins / Q000494:pharmacology; D007172:Erectile Dysfunction / Q000188:drug therapy*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008566:Membranes; D051379:Mice; D013948:Moxisylyte / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009603:Nitroso Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D010413:Penis / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D010656:Phenylephrine / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects / Q000378:metabolism; D014665:Vasodilator Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D015016:Yohimbine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000317:Adrenergic alpha-Antagonists; D016232:Endothelins; C120145:NMI 187; C120144:NMI 221; D009603:Nitroso Compounds; D018340:Receptors, Adrenergic, alpha-1; D014665:Vasodilator Agents; D010656:Phenylephrine; D015016:Yohimbine; D006152:Cyclic GMP; D013948:Moxisylyte