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Functional effects of the monoamine reuptake inhibitor, IPED2015 in both cerebral and erectile tissue in vitro

Comerma-Steffensen, S1; Munro, G2; Olesen, C3; Peters, D4; Simonsen, U1

1: Department of Biomedicine, Aarhus University, Denmark; 2: Department of Neurology, Glostrup Research Institute, Glostrup, Denmark; 3: Initiator Pharma A/S, Aarhus, Denmark; 4: DanPET AB, Malmö, Sweden

Objective(s). Erectile dysfunction where current drugs are insufficient is frequent, and new approaches are required to optimize the treatment. The present study investigated the cerebral and in vitro functional effects of a newly developed amine transport inhibitor, IPED2015.

Material and Method(s). Monoamine uptake was measured in synaptosomes from cortex, striatum and hippocampus in vitro and binding studies were performed after injection of radiolabeled ligands ([3H]-noradrenaline, [3H]-5-hydroxytyptamine, and [3H]WIN35,428] in vivo. Functional studies were performed in isolated corpus cavernosum strips.

Results. In vitro, IPED2015 inhibited uptake of 5-hydroxytryptamine and noradrenaline with low nanomolar potency, with in vitro dopamine uptake measured at ten-fold higher half-maximal concentrations (64 nM). In contrast, in vivo binding to the dopamine transporter (4.5 mg/kg) was 10-fold more potent than to the serotonin or noradrenaline transporter indicating that IPED2015 is preferentially a dopamine reuptake inhibitor. In corpus cavernosum strips at baseline tension, dopamine and IPED2015 induced concentration-dependent relaxations that were unchanged in the presence of a dopamine D2 antagonist, clozapine, and abolished in the presence of the D1 receptor antagonist, SCH23390. The IPED2015 relaxations were abolished by a nitric oxide synthase inhibitor, NG-nitro-L-arginine, and enhanced in the presence of a phosphodiesterase type 5 (PDE5) inhibitor, sildenafil. In phenylephrine-contracted preparations, IPED2015 at low concentrations (1-10 nM) further increased contraction, while 0.3-30 µM induced relaxations. Electrical field stimulation (16 Hz) induced contractions followed by relaxations, and these were unchanged in the presence of increasing concentrations of IPED2015.

Conclusions and Implications. IPED2015 is a triple monoamine uptake inhibitor, which preferentially binds to the dopamine transporter in cerebral tissue in vivo. IPED2015 has a dopamine D1 receptor-mediated relaxing effect on corpus cavernosum in vitro, which is enhanced by a PDE5 inhibitor. Thus, IPED2015 may act via both central and peripheral mechanisms to initiate erection. Moreover, it can modulate the effect of drugs with a peripheral mechanism of action on erectile function.

Disclosure:

Work supported by industry: yes, by Initiator Pharma (industry funding only - investigator initiated and executed study). The presenter or any of the authors act as a consultant, employee (part time or full time) or shareholder of an industry.

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