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

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

  • Br J Pharmacol. 2024 Apr 11. doi: 10.1111/bph.16362.
Simon Comerma-Steffensen 1 2 3,  Attila Kun 1,  Judit Prat-Duran 1,  Susie Mogensen 1,  Elif Alan Albayrak 1 4,  Rafael Fais 1 5,  Gordon Munro 6,  Dan Peters 3 7,  Ulf Simonsen 1 3
Affiliations

Affiliations

  • 1 Department of Biomedicine, Pulmonary and Cardiovascular Pharmacology, Aarhus University, Aarhus, Denmark.
  • 2 Department of Biomedical Sciences/Animal Physiology, Faculty of Veterinary, Central University of Venezuela, Caracas, Venezuela.
  • 3 Initiator Pharma A/S, Copenhagen, Denmark.
  • 4 Department of Pharmacology, Faculty of Pharmacy, Ege University, Izmir, Türkiye.
  • 5 Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
  • 6 Hoba Therapeutics, Copenhagen, Denmark.
  • 7 DanPET AB, Malmö, Sweden.
PMID: 38604613 DOI: 10.1111/bph.16362
Abstract

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.

Keywords

IP2015; dopamine; dopamine transporter; endothelium; erection; mice; rats.

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