A novel reuptake inhibitor, IP2015, induces erection by increasing central dopamine and peripheral nitric oxide release

• Published in: British journal of pharmacology 2024-08, Vol.181 (15), p.2566-2582
• Main Authors: Comerma‐Steffensen, Simon, Kun, Attila, Prat‐Duran, Judit, Mogensen, Susie, Alan Albayrak, Elif, Fais, Rafael, Munro, Gordon, Peters, Dan, Simonsen, Ulf
• Format: Article
• Language: English
• Subjects: Clozapine; Contractility; Diabetes; Diabetes mellitus; Dopamine; Dopamine D1 receptors; Dopamine D2 receptors; Dopamine transporter; Endothelial cells; endothelium; Erectile dysfunction; erection; IP2015; mice; Monoamine transporter; Nitric oxide; Nitric-oxide synthase; Norepinephrine; Penis; rats; Sildenafil; Sulpiride; Synaptosomes
• ISSN: 0007-1188; 1476-5381; 1476-5381
• DOI: 10.1111/bph.16362

Background and Purpose An estimated 40% of patients with erectile dysfunction have a poor prognosis for improvement with currently available treatments. The present study investigated whether a newly developed monoamine transport inhibitor, IP2015, improves erectile function. Experimental Approach We investigated the effects of IP2015 on monoamine uptake and binding, erectile function in rats and diabetic mice and the effect on corpus cavernosum contractility. Key Results IP2015 inhibited the uptake of 5‐HT, noradrenaline and dopamine by human monoamine transporters expressed in cells and in rat brain synaptosomes. Intracavernosal pressure measurement in anaesthetized rats revealed that IP2015 dose‐dependently increased the number and the duration of spontaneous erections. Whereas pretreatment with the dopamine D2‐like receptor antagonists, clozapine and (−)‐sulpiride, or cutting the cavernosal nerve inhibited IP2015‐induced erectile responses, the phosphodiesterase type 5 inhibitor sildenafil further enhanced the IP2015‐mediated increase in intracavernosal pressure. IP2015 also increased the number of erections in type 2 diabetic db/db mice. Direct intracavernosal injection of IP2015 increased penile pressure, and in corpus cavernosum strips, IP2015 induced concentration‐dependent relaxations. These relaxations were enhanced by sildenafil and blunted by endothelial cell removal, a nitric oxide synthase inhibitor, NG‐nitro‐l‐arginine and a D1‐like receptor antagonist, SCH23390. Quantitative polymerase chain reaction (qPCR) showed the expression of the dopamine transporter in the rat corpus cavernosum. Conclusion and Implications Our findings suggest that IP2015 stimulates erectile function by a central mechanism involving dopamine reuptake inhibition and direct NO‐mediated relaxation of the erectile tissue. This novel multi‐modal mechanism of action could offer a new treatment approach to erectile dysfunction.