Medicinal Chemistry with Pharmaceutical Product Development

Debarshi Kar Mahapatra, Sanjay Kumar Bharti, Debarshi Kar Mahapatra, Sanjay Kumar Bharti

• Publisher: Apple Academic Press
• Year: 2019
• eBook ISBN: 9780429947148
• Edition: 1
• Topic: Medicine
• Subtopic: Pharmacology

This volume focuses on novel therapeutics and strategies for the development of pharmaceutical products, keeping the drug molecule as the central component. It discusses current theoretical and practical aspects of pharmaceuticals for the discovery and development of novel therapeutics for health problems. Explaining the necessary features essential for pharmacological activity, it takes an interdisciplinary approach by including a unique combination of pharmacy, chemistry, and medicine along with clinical aspects. It takes into consideration the therapeutic regulations of the USP along with all the latest therapeutic guidelines put forward by WHO, and the US Food and Drug Administration.

CHAPTER 1

PROTEIN FUNCTION AS CELL SURFACE AND NUCLEAR RECEPTOR IN HUMAN DISEASES

URMILA JAROULIYA¹ and RAJ K. KESERVANI²

¹School of Studies in Biotechnology, Jiwaji University, Gwalior (M.P.), 474011, India

²School of Pharmaceutical Sciences, Rajiv Gandhi Proudyogiki Vishwavidyalaya, Bhopal (M.P.), 462036, India,

Mobile: [phone], E-mail: [email protected]

ABSTRACT

Protein is the major component of all cells in the body and plays numbers of functions in the biological world, from catalyzing chemical reactions to build the structures of all living things. Cell receptors are made up of protein and they play a major role in signal transduction. Out of the many cell receptors, the well-known G-protein-coupled receptors (GPCRs) represent the most important targets in modern pharmacology because of the different functions they mediate, especially within the brain and peripheral nervous system. Other GPCRs like β₁-adrenergic receptor (β₁AR) that plays a paramount role in chronic heart failure, 5-HT₄ receptor and acetylcholine receptor (AChR) has role in the treatment of Alzheimer’s disease (AD), N-methyl-D-aspartate receptor (NMDAR) is a stimuli for neuroautoimmune disorder, dopamine receptor (DAR) improves the stimulants in the treatment of Parkinson’s disease (PD), cannabinoid (CB1 and CB2) receptor in the brain, and are involved in a variety of physiological processes including appetite, pain-sensation, mood, and memory. Adenosine receptor (AR) on erythrocytes reduces the HbS oxygen affinity and promotes its polymerization and red blood cell sickling. Chemokine receptors are cytokine receptor that interacts with the leukocyte cells on the surface. Another category of receptor involves receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones, that phosphorylates the cascades of the various signaling pathways. The transforming growth factor-β (TGF-β) system signals via protein kinase receptors and regulates the biological processes, including morphogenesis, embryonic development, adult stem cells differentiation, immune regulation, wound healing, or inflammation. Signaling through platelet-derived growth factor (PDGF) receptors contribute to multiple tumors associated processes. The ErbB/HER protein-tyrosine kinases, which include the epidermal growth factor receptor, are associated with the development of neurodegenerative diseases, such as multiple sclerosis and Alzheimer’s disease. Insulin receptor (IR) plays a key role in glucose homeostasis. Among other receptors in plants, one of them is receptor-like kinases (RLKs) which control a wide range of processes, including development, disease resistance, hormone perception, and self-incompatibility in plants. Toll-like receptors (TLRs) are non-catalytic receptors expressed in sentinel cells and play a key role in the innate immune response to invading pathogens. Apart from cell surface receptors, there is a nuclear receptor (NR) that regulates transcription in response to small lipophilic compounds and plays a role in every aspect of development, physiology, and disease in humans. Nuclear receptor (NR) includes estrogen (ERNR), progesterone (PRNR), androgen (ARNR), Vitamin D (VDRNR), and thyroid hormone (TRNR) receptors. In this chapter, we focus mainly on a signaling pathway of various receptors and their significance in various human ailments.

1.1 INTRODUCTION

The receptors are the protein molecule, usually found in the cells’ plasma membrane; facing extracellular (cell surface receptors), cytoplasmic (cytoplasmic receptors), or in the nucleus (nuclear receptors). The chemical signals such as hormones, cytokines, growth factors, enzyme or any ligand bind to a receptor that is triggering changes in the function of the cellular activity by means of various signaling pathways, this process is called signal transduction. There are several receptor components present in the cell and can be classified into the following categories:

• G protein-coupled receptors: also known as seven transmembrane G-protein receptor that includes the receptors for several hormones and slow transmitters

• Receptor tyrosine kinase and enzyme-linked receptor: plasma membrane receptors that are also enzymes. When one of these receptors is activated by its extracellular ligand, catalyzes the production of an intracellular second messenger ex: the insulin receptor

• Nuclear receptors: When binding to their specific ligand (such as the hormone), alter the rate at which specific genes are transcribed and translated into cellular proteins. Steroid and thyroid hormone receptors are examples of such receptors.

• Ionotropic receptors: these are gated-ion channels in the plasma membrane that open and close in response to the binding of chemical ligands such as acetylcholine (nicotinic) and gamma-aminobutyric acid (GABA) and activation of these receptors, results in changes in ion movement across the membrane.

In this chapter, we focus on G protein-coupled receptor and the receptors involved in human diseases such as β₁-adrenergic receptor, acetylcholine receptor, dopamine receptor, growth receptor, plant receptor-like kinase, toll-like receptors, and the nuclear receptors.

1.2 G-PROTEIN-COUPLED RECEPTORS (GPCRS)

It is a cell surface receptor (membrane receptors or transmembrane receptors) that is made up of specialized integral membrane proteins that takes part in communication between the cell and the extracellular environment of the cell. It is a receptor with seven transmembrane helical segments and distributed across nearly all of the body’s organs and tissues. In the cell, GPCRs plays as a key role in signal transducers that makes GPCRs key regulatory elements in a broad range of normal and pathological processes [1]. In addition to the cell surface, GPCRs are present in the endoplasmic reticulum, Golgi apparatus, nuclear membrane and even inside the nucleus itself [2, 3, 4]. The variety of endogenous ligands (stimuli) activate GPCRs including biogenic amines, neuropeptides, amino acids, ions, hormones, chemokines, lipid-derived mediators, proteases peptides, proteins [5], protons (H⁺) and ions (Ca²⁺) [6]. GPCRs lacks internal enzymatic activity and are coupled to heterotrimeric guanosine nucleotide–binding protein (G protein), which consist of Gα, Gβ and Gγ subunits. The binding of ligand(s) stabilizes the occupied GPCR in an active signaling conformation during which the heterotrimeric G-proteins dissociate in GTP-bound Gα and Gβγ subunits (Figure 1.1). These regulate the activity of several enzymes such as adenylate cyclase, phospholipase C (PLC) isoforms and kinases, resulting in the generation of intracellular second messengers that control cellular functions, which are responsible for triggering different signaling responses [7].

FIGURE 1.1 (See color insert.) G-protein-coupled receptor (GPCR).

Phosphorylation and desensitization of the GPCRs bound signaling molecule were executed by G protein-coupled receptor kinases (GRKs) that are truly recognized as the kinases. GPCR bound signaling molecules are phosphorylated by GRKs that leads to the translocation and binding of β-arrestins to the receptors, which further inhibits G protein activation by blocking receptor-G protein coupling [8, 9]. This process also promotes signaling molecules bound GPCR internalization [10, 11, 12] Thus, the GRK catalyzed phosphorylation and binding of β-arrestin to the receptors are believed to be the common mechanism of GPCR desensitization [13, 14]. GPCR desensitization is important for maintaining homeostasis in the cell, as the impairment of the desensitization process could cause various diseases such as heart failure [15, 16], asthma [17], Parkinson’s disease [18], and autoimmune disease [19]. Thus, GRKs play an essential role in maintaining cells and tissues in normal states. Here we, discuss the GPCRs malfunctioning in concern to various human diseases such as cardiac disease, Alzheimer’s disease, autoimmune, and Parkinson’s disease.

1.2.1 ADRENERGIC RECEPTORS AND HEART FAILURE

It is a GPCR receptor. There are four forms of adrenergic receptors they are α₁, α₂, β₁, and β₂ defined by minute differences in their affinities and responses to a group of agonists and antagonists. Here we focus on the β₁-adrenergic receptors (β₁AR) that appear to be a common target of several agonistic autoantibody-diseases that lead to chronic heart failure. The β1AR is the most-abundant in the human heart, approaching 75% of the total number of receptors [20]. The β₁AR are coupled primarily to the heterotrimeric G protein (Gs), to stimulate adenylyl cyclase activity. This association generates intracellular cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) activation, which regulate cardiac contractility and heart rate [21]. The activity of cAMP/PKA is kept in check by the activity of cAMP phosphodiesterases (PDE) and protein phosphatases [22, 23, 24, 25], and the activation of these enzymes leads to the breakdown of cAMP and inactivation of PKA. During stress hormones released such as epinephrine (catecholamine) or the adrenaline, which binds to β₁AR and induce signaling by the activity of cAMP/PKA pathways that increases the cardiac activity and results in heart failure so the GRKs activity in the heart appears to play a critical role, especially in heart failure. Heart failure following chronic β₁AR stimulation is typically associated with a reduction of β₁AR-mediated regulatory amplitude due to an increase in baseline cAMP and a decrease in maximal chronotropic catecholamine response [26]. In general, the current management of heart failure includes the u...

Table of contents

• Cover
• Half Title
• Title Page
• Copyright Page
• Table of Contents
• About the Editors
• Contributors
• Abbreviations
• Preface
• Foreword
• 1. Protein Function as Cell Surface and Nuclear Receptor in Human Diseases
• 2. Islet Transplantation in Type 1 Diabetes: Stem Cell Research and Therapy
• 3. Novel Anti-Cancer Drugs Based on Hsp90 Inhibitory Mechanisms: A Recent Report
• 4. Nanosuspensions as Nanomedicine: Current Status and Future Prospects
• 5. Nanocarrier Technologies for Enhancing the Solubility and Dissolution Rate of API
• 6. Recent Perspectives of Chalcone-Based Molecules as Protein Tyrosine Phosphatase 1B (PTP-1B) Inhibitors
• 7. Briefing Therapeutic Approaches in Anticoagulant, Thrombolytic, and Antiplatelet Therapy
• 8. Insulin Therapy for Diabetes: Current Scenario and Future Perspectives
• 9. Emerging Potential of In Vitro Diagnostic Devices: Applications and Current Status
• Index