PT - JOURNAL ARTICLE AU - I. Sáenz de Tejada AU - D. S. Garvey AU - J. D. Schroeder AU - T. Shelekhin AU - L. G. Letts AU - A. Fernández AU - B. Cuevas AU - S. Gabancho AU - V. Martínez AU - J. Angulo AU - M. Trocha AU - P. Marek AU - P. Cuevas AU - S. W. Tam TI - Design and Evaluation of Nitrosylated α-Adrenergic Receptor Antagonists as Potential Agents for the Treatment of Impotence DP - 1999 Jul 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 121--128 VI - 290 IP - 1 4099 - http://jpet.aspetjournals.org/content/290/1/121.short 4100 - http://jpet.aspetjournals.org/content/290/1/121.full SO - J Pharmacol Exp Ther1999 Jul 01; 290 AB - We designed and evaluated a new class of molecules, nitrosylated α-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 α-adrenergic receptor antagonists (α-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 α-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 α2-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). α-Adrenergic receptor-binding studies showed similar binding affinities for the α-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. α-ARA and the nitrosylated compounds showed no pain-inducing activity as evaluated with the paw-lick model in mice. In summary, nitrosylated α-ARA have the dual functionalities of nitric oxide donors and α-ARA. These drugs induced penile erection in animals, suggesting their possible therapeutic value as agents for the local pharmacological treatment of impotence. The American Society for Pharmacology and Experimental Therapeutics