Candidate Molecule for Premature Ejaculation, DA-8031: In Vivo and In Vitro Characterization of DA-8031

• Published in: Urology (Ridgewood, N.J.) N.J.), 2011-04, Vol.77 (4), p.1006.e17-1006.e21
• Main Authors: Jeon, Hyung-Jun, Kim, Hae-Sun, Lee, Chan-Ho, Lee, Young-Gun, Choi, Seol-Min, Sohn, Yong-Sung, Shin, Chang-Yong, Kim, Junghoon, Shim, Hyun-Joo, Kang, Kyung-Koo, Ahn, Byoung-Ok, Kim, Soon-Hoe
• Format: Article
• Language: English
• Subjects: Animals; Benzofurans - pharmacology; Benzofurans - therapeutic use; Disease Models, Animal; Dopamine Plasma Membrane Transport Proteins - metabolism; Ejaculation; Male; Neurotransmitter Uptake Inhibitors - pharmacology; Neurotransmitter Uptake Inhibitors - therapeutic use; Norepinephrine Plasma Membrane Transport Proteins - metabolism; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Adrenergic - drug effects; Receptors, Dopamine - drug effects; Receptors, Muscarinic - drug effects; Serotonin Plasma Membrane Transport Proteins - metabolism; Serotonin Uptake Inhibitors - pharmacology; Serotonin Uptake Inhibitors - therapeutic use; Sexual Dysfunction, Physiological - drug therapy; Symporters - metabolism; Urology
• ISSN: 0090-4295; 1527-9995
• DOI: 10.1016/j.urology.2010.11.046

Objectives To evaluate the efficacy of DA-8031 against premature ejaculation, we performed in vitro and in vivo pharmacologic studies. Methods We used a monoamine transporter binding affinity assay, receptor binding affinity assay, monoamine reuptake inhibition assay, and serotonin uptake inhibition assay in platelets and chemically induced ejaculation models in rats. Results The present study reports on the pharmacologic profile of the putative antipremature ejaculation drug, DA-8031. DA-8031 exhibits high affinity and selectivity to the serotonin transporter (Ki value 1.94 nM for 5-hydroxytryptamine transporter, 22 020 nM for norepinephrine transporter, and 77 679 nM for dopamine transporter) and potency to inhibit serotonin reuptake into the rat brain synaptosome in vitro (half maximal inhibitory concentration 6.52 nM for 5-hydroxytryptamine, 30.2 μM for norepinephrine, and 136.9 μM for dopamine). In the platelet serotonin uptake study, DA-8031 exhibited significant inhibition at oral doses of 10 and 30 mg/kg in a dose-dependent manner. In the sexual response studies, after oral and intravenous administration of DA-8031, ejaculation was significantly inhibited in both para-chloroamphetamine- and meta-chlorophenylpiperazine-mediated ejaculation models in rats. Conclusions The pharmacologic profiles observed in the present study suggest the potential for DA-8031 as a therapeutic agent useful in the treatment of premature ejaculation.