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1.1 Allosteric Modulation – A Historical Perspective Early ideas regarding allosterism emerged over 50 years ago, but gained little traction in the receptor field due to limitations in molecular pharmacology and screening technology.1,2 Allosterism is a critical biochemical mechanism, as it enables proteins to sense changes in their environment and respond to them; Fenton has recently referred to this as ‘second secret of life’, preceded only by the genome.1–3 The term allostery comes from the Greek allos ( λλoς), “other”, and stereos (στeρeOς), “solid (object)”, meaning that an allosteric site of a regulatory protein is physically distinct from the classic, active, site.1–4–8 In terms of receptor-based small molecule drug discovery, the binding site for the endogenous ligand is referred to as the orthosteric site.1,4–8 In this setting, an allosteric modulator is a small molecule that binds at a topographically distinct allosteric site, and either potentiates or inhibits the binding and/or signaling of an orthosteric ligand.1,4–8 Fueled by the clinical success of the first allosteric modulator drugs 1–4 (benzodiazepines, referred to as ‘benzo’ or BZD), which potentiate the effect of the neurotransmitter γ-aminobutyric acid (GABA) at the ionotropic GABAA receptor, the concept of allosteric modulation for a wide range of molecular targets has gained momentum in modern drug discovery (Figure 1).4,9 Benzodiazepines, for example, possess a number of modes of pharmacology and include positive allosteric modulators (PAMs), which potentiate GABAA receptor response, negative allosteric modulators (NAMs), which decrease channel activity and modulate the ability of these GABAergic receptors to elicit sedative, hypnotic, and anxiolytic effects. In addition to PAMs and NAMs, silent allosteric modulators (SAMs, or neutral allosteric ligands) bind at allosteric sites and can block the activity of PAMs and NAMs but, importantly, have no effect on orthosteric ligand responses. In contrast to the potentially deadly effects of direct acting GABAA agonists, allosteric modulation of GABAA by the benzodiazepine class has proven clinically safe and effective.4,9 With advances in molecular pharmacology and screening technology, allosteric modulators have now been developed for other ion channels, kinases, phospholipases and 7 Transmembrane Spanning Receptors (7TMRs, also known as G protein-coupled receptors (GPCRs)).1,4–8,10–15    Figure 1  Benzodiazepines, the first allosteric modulators with clinical success, and marketed as GABAA allosteric modualtors. A generic benzodiazepine scaffold 1 highlighting the classical substitution patterns. 2 (Librium™) was the first benzodiazepine ...     1.2 7TMRs Structure and Ligands 7TMRs are the largest class of cell surface receptors, accounting for over 30% of currently marketed drugs and over 50% of all known drugs.4–7 7TMRs are plasma membrane proteins that receive stimuli (in the form of hormones, neurotransmitters, light, ions or odorants) on the extracellular surface to alter receptor conformation, which in turn activates signaling cascades and effector systems located within the intracellular cytosol via coupling to G proteins and other accessory proteins.4–7 Much of our understanding of the basic structure and function of 7TMRs is based on biochemical, genetic, imaging, and molecular pharmacological research, as crystal structures of 7TMRs (Rhodopsin, opsin, beta2 and beta 1 (agonist and antagonist bound), dopamine D3, Adenosine 2A (agonist and antagonist bound), chemokine CXCR4, histamine H1) have only recently been solved definitively.4–7,16–32 However, these crystal structures have powered the development of homology models for multiple 7TMRs, and afforded avenues for ligand design efforts. Structurally, all 7TMRs possess seven transmembrane helices, three extracellular and three intracellular loops, with an extracellular N-terminal tail and an intracellular C-terminal tail (Figure 2).4–7,16–32 The heptahelical transmembrane domain is largely hydrophobic whereas the extracellular (e1–e3) and intracellular (i1–i3) segments, or loops, are generally hydrophilic as would be anticipated for amino acids exposed to the phospholipid-rich membrane and the water-rich environments, respectively. The seven transmembrane helices are each approximately two-dozen amino acids long, while the C- and N-terminal tails as well as the loops can vary widely in length with up to hundreds of amino acids.4–7,16–32 Based on sequence homology and functional roles, 7TMRs commonly divided into three main Families (or classes): A (e.g., M1 mAChR), B (e.g., CRF1) and C (e.g., mGlu5) (Figure 2). The families are readily distinguished by comparing their amino acid sequences; Family B are distinguished from Family A by the presence of a larger extracellular loop and Family C have a large, bi-lobed N-terminal Venus Fly Trap (VFT) domain. A second major difference between the families concerns the location of the orthosteric binding site and the nature of the orthosteric ligand. As shown in Figure 2, the orthosteric binding site of many Family A 7TMRs is located with the 7TM domain whereas the orthosteric binding site is located in the large extracellular loop within Family B and within the VFT domain in Family C. The orthosteric ligands for Family A and C are neurotransmitters, for example, 5 (acetylcholine, for the mAChRs) and 9 (glutamate, for the mGluRs), respectively.4–7 The orthosteric ligands for Family B 7TMRs are large peptide ligands with usually >30 amino acids, such as the 41 amino acid peptide 7 (hCRF) for corticotrophin releasing factor 1 (CRF1). In contrast, allosteric ligands are structurally distinct from orthosteric ligands and bind at distinct sights, often, but not always, topologically distant from the orthosteric site.4–7 For example, the Family A M1 mAChR PAM 6 (BQCA),33 is believed to bind in a region above the TMs among the extracellular loops, whereas the Family B PAM, 8 (DMP696),34 and the Family C NAM, 10 (MPEP),35,36 bind within the TM domains.    Figure 2  Structural topology of typical orthosteric and allosteric sites of Family A, B and C 7TMRs, highlighting representative orthosteric and allosteric ligands for each Family.    Are there naturally occurring allosteric modulators? This question is invariably posed during any discussion of allosteric modulators, and one must understand the complexity of identifying such ligands within the chemical diversity of ligands within the human body.1,2,37 However, a few natural allosteric modulators have been described, including the unnatural amino acid D-serine (an allosteric modulator of the NMDA receptor),38 L-phenylalanine and L-tryptophan (allosteric modulators of the calcium receptor)39 and the tetrepeptide Leu-Ser-Ala-Leu, also known as 5-HT moduline (an allosteric modulator of the 5-HT1B receptor).40,41

Allosteric Modulation of Seven Transmembrane Spanning Receptors: Theory, Practice, and Opportunities for Central Nervous System Drug Discovery