Novel 3,4-dihydropyrazino[1,2-b]indazol-1(2H)-one derivatives targeting serotonin 2A and adrenergic alpha1 receptors as ocular antihypertensive agents

The prolonged elevation of the intraocular pressure (IOP) is one of the main risk factor associated with Glaucoma. As a consequence, the current available pharmacological strategies for the treatment of this pathology (e. g. Prostaglandin F2alpha analogues, adrenergic beta blockers and carbonic anhydrase inhibitors) are essentially aimed to reduce IOP level. Unfortunately all these medical treatments are associated with relevant side effects or have significant percentage of non-responders, with the result that more than 50% of the patients failed to control the glaucoma progression. With the aim to develop novel lead compounds, without the important drawbacks of the existing drugs, we envisaged that the dual interaction with serotonin 2A (5-HT2A) and adrenergic alpha1 (α1) receptor could be a potential approach for ocular antihypertensive. This hypothesis is substantiate by the well-established effect of the two receptor systems on aqueous humour dynamic. In this work we briefly describe the discovery of the novel class of selective 5-HT2A receptor ligands (I) with balanced affinity for adrenergic α1 receptors. The general synthetic pathway used for the preparation of this class of compounds and the binding assay results of some representative products are showed. Moreover, we demonstrate the in vivo IOP reduction efficacy of one 3,4-dihydropyrazino[1,2-b]indazol-1(2H)-one derivative, by means of an ocular hypertensive rabbit model (carbomer model).