RT Journal Article SR Electronic T1 Design and Evaluation of Nitrosylated α-Adrenergic Receptor Antagonists as Potential Agents for the Treatment of Impotence JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 121 OP 128 VO 290 IS 1 A1 I. Sáenz de Tejada A1 D. S. Garvey A1 J. D. Schroeder A1 T. Shelekhin A1 L. G. Letts A1 A. Fernández A1 B. Cuevas A1 S. Gabancho A1 V. Martínez A1 J. Angulo A1 M. Trocha A1 P. Marek A1 P. Cuevas A1 S. W. Tam YR 1999 UL http://jpet.aspetjournals.org/content/290/1/121.abstract 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