Synthesis and binding affinity evaluation of new bitopic ligands of the mu opioid receptor (MOR)

Opioid receptors represent one of the most important targets in the treatment of acute and chronic pain. However, activation of this class of receptors leads to serious and sometimes lethal side effects such as respiratory depression. A few hypotheses including low intrinsic G protein efficacy and functional selectivity of some ligands have been proposed and investigated for the development of the side effects. Nonetheless, the molecular basis governing the side effect profile of opioid receptors still remains unclear. This is reflective of the need for new pharmacological tool compounds to study this class of receptors in order to gain valuable insight into their mechanism of action which can assist in the engineering of improved opioids with fewer undesired effects. In this regard, bitopic ligands of the mu opioid receptor (MOR) which simultaneously bind the orthosteric and allosteric binding sites were designed and synthesised. From previous studies in the working group with muscarinic receptors, bitopic ligands showed interesting properties such as subtype and functional selectivity.The proof of concept developed for muscarinic receptors was thus applied to the MOR in order to obtain valuable information into its mechanism of action and/or biased signalling. The bitopic ligands were designed based on the positive allosteric modulator (PAM) BMS-986122 as the allosteric block and the agonists PZM21 and TRV130 as orthosteric moieties. In the design of these ligands, suitable linker attachment points on both the allosteric and orthosteric moieties were identified. Subsequently, the synthesis of these compounds was adapted to allow the introduction of the linker prior to attempting the tethering of the allosteric and orthosteric blocks to obtain the bitopic ligands.