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Current Topics in Medicinal Chemistry, 2019, 19, 1399-1417 REVIEW ARTICLE Send Orders for Reprints to [email protected] 1399 Current Topics in Medicinal Chemistry, 2019, 19, 1399-1417 REVIEW ARTICLE ISSN: 1568-0266 eISSN: 1873-4294 Impact Factor: Targeting the PAC1 Receptor for Neurological and Metabolic Disorders 3.442 The international journal for in-depth reviews on Current Topics in Medicinal Chemistry BENTHAM SCIENCE Chenyi Liao1, Mathilde P. de Molliens2, Severin T. Schneebeli1, Matthias Brewer1, Gaojie Song3, David Chatenet2, Karen M. Braas4, Victor May4,* and Jianing Li1,* 1Department of Chemistry, University of Vermont, Burlington, VT 05405, USA; 2INRS – Institut Armand-Frappier, 531 boul. des Prairies, Laval, QC H7V 1B7, Canada; 3Shanghai Key Laboratory of Regulatory Biology, Institute of Bio- medical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, P.R. China; 4Department of Neurological Sciences, University of Vermont, Larner College of Medicine, 149 Beaumont Avenue, Bur- lington, VT 05405, USA Abstract: The pituitary adenylate cyclase-activating polypeptide (PACAP)-selective PAC1 receptor (PAC1R, ADCYAP1R1) is a member of the vasoactive intestinal peptide (VIP)/secretin/glucagon fam- ily of G protein-coupled receptors (GPCRs). PAC1R has been shown to play crucial roles in the central and peripheral nervous systems. The activation of PAC1R initiates diverse downstream signal transduc- tion pathways, including adenylyl cyclase, phospholipase C, MEK/ERK, and Akt pathways that regu- late a number of physiological systems to maintain functional homeostasis. Accordingly, at times of tissue injury or insult, PACAP/PAC1R activation of these pathways can be trophic to blunt or delay apoptotic events and enhance cell survival. Enhancing PAC1R signaling under these conditions has the potential to mitigate cellular damages associated with cerebrovascular trauma (including stroke), neu- A R T I C L E H I S T O R Y rodegeneration (such as Parkinson’s and Alzheimer's disease), or peripheral organ insults. Conversely, maladaptive PACAP/PAC1R signaling has been implicated in a number of disorders, including stress- Received: December 04, 2018 related psychopathologies (i.e., depression, posttraumatic stress disorder, and related abnormalities), Revised: December 23, 2018 chronic pain and migraine, and metabolic diseases; abrogating PAC1R signaling under these pathologi- Accepted: December 26, 2018 cal conditions represent opportunities for therapeutic intervention. Given the diverse PAC1R-mediated DOI: 10.2174/1568026619666190709092647 biological activities, the receptor has emerged as a relevant pharmaceutical target. In this review, we first describe the current knowledge regarding the molecular structure, dynamics, and function of PAC1R. Then, we discuss the roles of PACAP and PAC1R in the activation of a variety of signaling cascades related to the physiology and diseases of the nervous system. Lastly, we examine current drug design and development of peptides and small molecules targeting PAC1R based on a number of struc- ture-activity relationship studies and key pharmacophore elements. At present, the rational design of PAC1R-selective peptide or small-molecule therapeutics is largely hindered by the lack of structural information regarding PAC1R activation mechanisms, the PACAP-PAC1R interface, and the core segments involved in receptor activation. Understanding the molecular basis governing the PACAP interactions with its different cognate receptors will undoubtedly provide a basis for the development and/or refinement of receptor-selective therapeutics. Keywords: Class B GPCR, Behavioral disorders, Neurodegenerative diseases, Molecular modeling, Structure-based drug dis- covery, PAC1 Receptor. 1. INTRODUCTION cretin (class B), glutamate (class C), adhesion, and friz- zled/taste. Although consisting of only 15 known members, G Protein-coupled Receptors (GPCRs) represent the larg- the class B GPCRs are activated by a number of critical est and one of the most important receptor families for drug regulatory peptides, such as corticotropin-releasing hormone discovery. The approximate 800 heptahelical receptor (CRH), calcitonin gene-related peptide (CGRP), parathyroid members can be divided into five major classes based on hormone (PTH), glucagon, vasoactive intestinal peptide sequence and structural similarities: rhodopsin (class A), se- (VIP), and pituitary adenylate cyclase-activating polypeptide (PACAP, ADCYAP1). These peptides are important with respect to neural development, calcium homeostasis, glucose *Address correspondence to these authors at the Department of Chemistry, University of Vermont, 82 University Place, Burlington, VT 05405, USA; metabolism, circadian rhythm, thermoregulation, inflamma- E-mail: [email protected] and Department of Neurological Sciences, tion, feeding behavior, pain modulation, as well as stress and University of Vermont, Larner College of Medicine, 149 Beaumont Avenue, related endocrine responses [1-3]. Accordingly, their corre- Current Topics in Medicinal Chemistry Burlington, VT 05405, USA; E-mail: [email protected] sponding receptors are potential pharmacological targets for 1873-4294/19 $58.00+.00 © 2019 Bentham Science Publishers 1400 Current Topics in Medicinal Chemistry, 2019, Vol. 19, No. 16 Liao et al. a variety of disorders including osteoporosis, hypercalcemia, intracellular and three extracellular loops (Fig. 2). Singu- type 2 diabetes, obesity, migraine, and related chronic pain larly, class B GPCRs have an N-terminal extracellular do- disorders, as well as stress-associated psychopathologies, main (ECD) composed of 120 to 160 residues which appear including depression [4-7], posttraumatic stress disorder critical for the recognition of the C-terminal regions of pep- (PTSD), and related anxiety-related abnormalities [8-10]. tide ligands [4]. Atomic structures of eleven of the fifteen ECDs have been determined by X-ray crystallography or In this review, we focus on one specific class B GPCR, nuclear magnetic resonance (NMR), either with or without the PACAP receptor (PAC1R, ADCYAP1R1, Fig. 1), which their peptide ligands in the complex. Notably, these struc- is highly expressed in the central and peripheral nervous tures reveal a similar arrangement of a three-layered α-β-β/α systems. PAC1R is activated by the alternatively posttransla- fold [5] as well as a conserved peptide binding interface [6] tionally processed PACAP neuropeptides (PACAP27 or PACAP38). PAC1R is dually coupled to Gs or Gq to stimu- (Fig. 2). The 7TM structures for three class B receptors, the glucagon receptor (GCGR) [7-8], the glucagon-like peptide 1 late adenylyl cyclase (AC)/cAMP or phospholipase C receptor (GLP-1R) [9], and the corticotrophin-releasing fac- (PLC)/DAG/IP3 pathways, respectively, and can engage tor receptor 1 (CRF1R) [10] have been determined. These other signaling programs in endosomal compartments fol- structures provide templates to model peptide and allosteric lowing receptor internalization. We first review the current modulator interactions within the 7TM and have enabled knowledge regarding the molecular structure, motion, and function of PAC1R and its peptide-binding modes. Then, we initial, structure-based interpretations of SARs. The recently published full-length crystal structures of peptide bound discuss the roles of PACAP/PAC1R in homeostatic and mal- GLP-1R [11] and antibody or peptide bound GCGR [12, 13] adaptive signaling. Lastly, we examine current approaches to reveal how the peptides can bind to the orthosteric pockets the design and development of peptide and small-molecule within the 7TM to trigger downstream signaling cascades. antagonists of PAC1R based on structure-activity relation- Further, the cryo-electron microscopy (cryo-EM) structures ship (SAR) studies and key pharmacophore elements, which could have broad impacts on many physiological systems. of GLP-1R [14, 15] and Calcitonin Receptor (CTR) [16] and CGRP receptor [17] bound to their downstream Gs trimeric complex reveal how the class B GPCR 7TMs undergo con- 2. PAC1R STRUCTURE, FUNCTION, AND DYNAM- formational changes at their intracellular regions (from TM5 ICS to helix 8) to allow G protein binding and signaling. The 2.1. Structures of Class B GPCRs and PAC1R binding poses of Gαs with TM5-TM6 of class A and class B GPCRs are similar, but the class B GPCRs have helix 8 in The common basic structure of GPCRs consists of a hep- the cytoplasmic tail segment, tilted (~25o) to enable addi- tahelical-transmembrane domain (7TM) tethered by three tional interactions with the Gβ subunit. Overall, these struc- Fig. (1). A schematic diagram of PAC1R signaling cascades. Activation of the PAC1R is dually coupled to Gs to stimulate adenylyl cyclase (AC) and Gq to stimulate phospholipase C (PLC) activity. The increase in cellular cAMP can stimulate protein kinase A (PKA)/EPAC path- ways that can intersect and enhance MEK/ERK signaling. PAC1R activation and recruitment of β-arrestin also result in receptor internaliza- tion and formation of endosomal signaling platforms for long-term MEK/ERK signaling. Targeting the PAC1 Receptor for Neurological and Metabolic Disorders Current Topics in Medicinal Chemistry, 2019, Vol. 19, No. 16 1401 tures have extended understandings of ligand-receptor inter- ing conformations [22-29]. In recent years, an understanding actions and orthosteric versus allosteric modulation mecha- of the structural basis and dynamic details of class B recep- nisms of class B GPCRs and have provided the underlying tors
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