Design, synthesis and in vitro evaluation of a Dopa-organoboron compound that acts as a bladder relaxant through non-catecholamine receptors

Bladder relaxation through drug administration is an interesting topic in medicinal and combinatorial chemistry. In fact, compounds targeting catecholamine receptors [dopamine receptors and beta-adrenergic receptors (βAR) expressed in the bladder] are among the compounds commonly employed for this purpose. In particular, recent investigations have tended to focus on the β3-adrenoceptor (β3AR) as a target in the treatment of urinary incontinence and other disorders. However, organoboron compounds have been suggested as potent and efficient agents on these drug targets. In this work, through a docking study, we identified the parameters that induce a theoretical improvement in the affinity and activity of the organoboron compounds on the catecholamine receptors expressed in the bladder. Then, the identified potential drug, a boron-containing dopa-derivative named DPBX-l-Dopa, was synthesized and characterized. This compound induces a relaxation on the smooth muscle of the rat bladder, behaving as a weak relaxant compared to isoproterenol but with similar efficacy to BRL377, a selective β3AR agonist. However, unexpectedly, this effect was not blocked by propranolol or haloperidol at the concentrations at which they are able to block the catecholamine receptors in bladder tissue. In view of these results, the effect of DPBX-l-Dopa compound on the alpha 1 adrenergic receptors (α1AR) of aorta of the rats was also explored; however, no response of the tissue to this compound was obtained. The possible mechanisms of the action of this compound were explored and are discussed further.