The preclinical pharmacology of BIBN4096BS, a CGRP antagonist

CGRP is an important neuropeptide found throughout the cardiovascular system. However, until recently it has been difficult to define its pharmacology or physiological role because of the lack of suitable antagonists. BIBN4096BS is a high-affinity, nonpeptide antagonist that shows much greater selectivity for human CGRP1 receptors compared to any other drug. Its pharmacology has been defined with studies on transfected cells or cell lines endogenously expressing receptors of known composition. These have allowed confirmation that in many human blood vessels, CGRP is working via CGRP1 receptors. However, it also interacts with other CGRP-activated receptors, of unknown composition. In vivo, clinical studies have shown that BIBN4096BS is likely to be useful in the treatment of migraine. It has also been used to define the role of CGRP in phenomena such as plasma extravasation and cardioprotection following ischemia.

Modulation of glucagon receptor pharmacology by Receptor Activity-modifying Protein-2 (RAMP2)

The glucagon and glucagon-like peptide-1 (GLP-1) receptors play important, opposing roles in regulating blood glucose levels. Consequently, these receptors have been identified as targets for novel diabetes treatments. However, drugs acting at the GLP-1 receptor, whilst having clinical efficacy, have been associated with severe adverse side-effects and targeting of the glucagon receptor has yet to be successful. Here we use a combination of yeast reporter assays and mammalian systems, to provide a more complete understanding of glucagon receptor signaling considering the effect of multiple ligands, association with the receptor-interacting protein, receptor activity modifying protein-2 (RAMP2) and individual G protein α-subunits. We demonstrate that RAMP2 alters both ligand selectivity and G protein preference of the glucagon receptor. Importantly, we also uncover novel cross-reactivity of therapeutically used GLP-1 receptor ligands at the glucagon receptor that is abolished by RAMP2 interaction. This study reveals the glucagon receptor as a previously unidentified target for GLP-1 receptor agonists and highlights a role for RAMP2 in regulating its pharmacology. Such previously unrecognized functions of RAMPs highlight the need to consider all receptor-interacting proteins in future drug development.

Pharmacology and the safe prescribing of drugs

Understanding the pharmacological principles and safe use of drugs is just as important in surgical practice as in any other medical specialty. With an ageing population with often multiple comorbidities and medications, as well as an expanding list of new pharmacological treatments, it is important that surgeons understand the implications of therapeutic drugs on their daily practice. The increasing emphasis on high quality and safe patient care demands that doctors are aware of preventable adverse drug reactions (ADRs) and interactions, try to minimize the potential for medication errors, and consider the benefits and harms of medicines in their patients. This chapter examines these aspects from the view of surgical practice and expands on the implications of some of the most common medical conditions and drug classes in the perioperative period. The therapeutic care of surgical patients is obvious in many circumstances – for example, antibacterial prophylaxis, thromboprophylaxis, and postoperative analgesia. However, the careful examination of other drug therapies is often critical not only to the sustained treatment of the associated medical conditions but to the perioperative outcomes of patients undergoing surgery. The benefit–harm balance of many therapies may be fundamentally altered by the stress of an operation in one direction or the other; this is not a decision that should wait until the anaesthetist arrives for a preoperative assessment or one that should be left to junior medical or nursing staff on the ward.

Pharmacology and therapeutic implications of current drugs for type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM) is a global epidemic that poses a major challenge to health-care systems. Improving metabolic control to approach normal glycaemia (where practical) greatly benefits long-term prognoses and justifies early, effective, sustained and safety-conscious intervention. Improvements in the understanding of the complex pathogenesis of T2DM have underpinned the development of glucose-lowering therapies with complementary mechanisms of action, which have expanded treatment options and facilitated individualized management strategies. Over the past decade, several new classes of glucose-lowering agents have been licensed, including glucagon-like peptide 1 receptor (GLP-1R) agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors and sodium/glucose cotransporter 2 (SGLT2) inhibitors. These agents can be used individually or in combination with well-established treatments such as biguanides, sulfonylureas and thiazolidinediones. Although novel agents have potential advantages including low risk of hypoglycaemia and help with weight control, long-term safety has yet to be established. In this Review, we assess the pharmacokinetics, pharmacodynamics and safety profiles, including cardiovascular safety, of currently available therapies for management of hyperglycaemia in patients with T2DM within the context of disease pathogenesis and natural history. In addition, we briefly describe treatment algorithms for patients with T2DM and lessons from present therapies to inform the development of future therapies.

An allosteric role for receptor activity-modifying proteins in defining GPCR pharmacology

G protein-coupled receptors are allosteric proteins that control transmission of external signals to regulate cellular response. Although agonist binding promotes canonical G protein signalling transmitted through conformational changes, G protein-coupled receptors also interact with other proteins. These include other G protein-coupled receptors, other receptors and channels, regulatory proteins and receptor-modifying proteins, notably receptor activity-modifying proteins (RAMPs). RAMPs have at least 11 G protein-coupled receptor partners, including many class B G protein-coupled receptors. Prototypic is the calcitonin receptor, with altered ligand specificity when co-expressed with RAMPs. To gain molecular insight into the consequences of this protein–protein interaction, we combined molecular modelling with mutagenesis of the calcitonin receptor extracellular domain, assessed in ligand binding and functional assays. Although some calcitonin receptor residues are universally important for peptide interactions (calcitonin, amylin and calcitonin gene-related peptide) in calcitonin receptor alone or with receptor activity-modifying protein, others have RAMP-dependent effects, whereby mutations decreased amylin/calcitonin gene-related peptide potency substantially only when RAMP was present. Remarkably, the key residues were completely conserved between calcitonin receptor and AMY receptors, and between subtypes of AMY receptor that have different ligand preferences. Mutations at the interface between calcitonin receptor and RAMP affected ligand pharmacology in a RAMP-dependent manner, suggesting that RAMP may allosterically influence the calcitonin receptor conformation. Supporting this, molecular dynamics simulations suggested that the calcitonin receptor extracellular N-terminal domain is more flexible in the presence of receptor activity-modifying protein 1. Thus, RAMPs may act in an allosteric manner to generate a spectrum of unique calcitonin receptor conformational states, explaining the pharmacological preferences of calcitonin receptor-RAMP complexes. This provides novel insight into our understanding of G protein-coupled receptor-protein interaction that is likely broadly applicable for this receptor class.