Vol. 290, Issue 1, 121-128, July 1999

Design and Evaluation of Nitrosylated -Adrenergic Receptor Antagonists as Potential Agents for the Treatment of Impotence¹

I. Sáenz de Tejada, D. S. Garvey, J. D. Schroeder, T. Shelekhin, L. G. Letts, A. Fernández, B. Cuevas, S. Gabancho, V. Martínez, J. Angulo, M. Trocha, P. Marek, P. Cuevas and S. W. Tam

Departamento de Investigación, Hospital Ramón y Cajal, Fundación para la Investigación y el Desarrollo en Andrología, Madrid, Spain (I.S. de T., A.F., B.C., S.G., V.M., J.A., P.C.); and NitroMed, Inc., Bedford, Massachusetts (D.S.G., J.D.S., T.S., L.G.L., M.T., P.M.)

We designed and evaluated a new class of molecules, nitrosylated -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 -adrenergic receptor antagonists (-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 -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 ₂-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). -Adrenergic receptor-binding studies showed similar binding affinities for the -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. -ARA and the nitrosylated compounds showed no pain-inducing activity as evaluated with the paw-lick model in mice. In summary, nitrosylated -ARA have the dual functionalities of nitric oxide donors and -ARA. These drugs induced penile erection in animals, suggesting their possible therapeutic value as agents for the local pharmacological treatment of impotence.