Abstract:
Small molecule modulators of the adrenomedullin 1 receptor Lydia P. Liew1, Erica R. Burns2, Muhammad A. Jamaluddin2, Muriel Bonnet1, Jack U. Flanagan1, Debbie L. Hay2, Michael P. Hay1 1Auckland Cancer Society Research Centre, University of Auckland, Auckland 1142, NZ, 2School of Biological Sciences, University of Auckland, Auckland 1142, NZ. Adrenomedullin (AM) is widely expressed in a range of tissue types with particularly interesting effects on vasculature and cellular growth. AM mediates contrasting responses in a pathology dependent manner. For example, increased AM levels have protective effects on the cardiovascular system in hypertension and heart failure. Yet in cancer, AM promotes angiogenesis to increase oxygen and nutrient delivery and so support tumour growth. Consequently, there is considerable interest in the identification of modulators of the AM pathway. The effects of AM are predominantly mediated through the AM1 receptor, which consists of two subunits: the calcitonin receptor-like receptor (CLR) (a G protein-coupled receptor) and receptor activity-modifying protein (RAMP2). A closely related receptor, the calcitonin gene-related peptide (CGRP) receptor has been the focus of extensive drug discovery efforts, through which a family of CGRP receptor antagonists (e.g., telcagepant, olcegepant) with clinical activity against migraine has been identified. We used structural information from the crystal structures of AM1 and CGRP extra-cellular domain (ECD) complex to design small molecules that are selective for the AM1 receptor. We mimicked interactions of the antagonist telcagepant at the CGRP receptor through the use of a benzimidazolone motif to bind to THR122 of the CLR subunit. This motif was then elaborated with a variety of chemotypes to impart selectivity towards the AM1 receptor. Activity at the AM1 and CGRP receptors were evaluated using a combination of cAMP and β-arrestin recruitment assays. All compounds were independently screened ( n=2) in the absence and presence of AM or CGRP to check for modulator activity or peptide-independent activity. We have identified a series of AM1 receptor selective small molecules which appear to act as positive allosteric modulators of AM activity, rather than antagonists. We report our exploration of this class of AM1 modulators, which represent first-in-class molecules.