Receptors as Drug Targets
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Abstract
Receptors, located on both the cell surface and within the cell, are the molecular targets through which drugs produce their beneficial effects in various disease states. Receptors were initially conceptualized at the beginning of the 20th century by the parallel efforts of Ehrlich and Langley. The concepts of the receptor and receptor theory, based on the Law of Mass Action, have undergone continuous refinement as they have been characterized in terms of their molecular structure, association with ancillary proteins (e.g., G proteins, arrestins, RAMPs), and functional characteristics in normal and diseased tissues. The concepts describing ligand interactions with receptors have also been refined from the simple binary concept of competitive agonists and antagonists to partial agonists, allosteric modulators and inverse agonists. Concepts such as receptor constitutive activity, internalization and dimerization add additional complexity to the role of receptors in tissue function and in precisely characterizing their role in homeostasis and disease.
Keywords: agonist; antagonist allosteric modulator; G protein?coupled receptor; heterotrimeric G protein; ion channels; ligand; new chemical entity (NCE); orphan receptor; structure activity relationship (SAR)
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PDF or HTML at Wiley Online LibraryTable of Contents
- Receptor Classification and Nomenclature
- Receptor Structure and Motifs
- Receptor Ligands
- Constitutively Active Receptors
- Ligand‐Receptor Interactions
- Orphan Receptors
- Neurotransmitters, Neurohormones, and Neuromodulators
- Allosteric Ligands
- Human Recombinant Receptors
- Receptor Mutations and Chimeras
- Assessing Receptor Function
- Literature Cited
- Figures
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Figure 1.1.1 Structural motifs of various receptor classes. (A ) GPCR with seven membrane‐spanning regions; (B‐E ) LGICs: (B ) glutamate receptor, (C ) P2X receptor, (D ) nAChR, and (E ) VGIC K+ ‐rectified inward (Kirs) receptor; (F ) STAT receptor; (G ) PTK growth factor receptor; (H ) neutrophin receptor ( trk ). View Image -
Figure 1.1.2 Ligand efficacy spectrum. View Image -
Figure 1.1.3 (A ) Schematic of a saturation binding curve: total, nonspecific, and specific binding (see UNIT ). (B ) Scatchard derivation of specific binding saturation isotherm. (C ) Ligand displacement curve showing IC50 relationship. (D ) Ligand efficacy and EC50 derivation. The EC50 for a partial agonist (EC50 B) can be determined as the concentration at which a similar response to that of a full agonist (EC50 A) is observed. Alternatively, the EC50 for a partial agonist can be determined as the concentration at which 50% of the maximal response to the partial agonist is determined (EC50 C). Clearly, using the latter approach in the absence of any measure of ligand potency (receptor affinity) can provide misleading data. (E ) Dose‐response relationship in the presence of increasing concentrations ( X‐Z ) of an antagonist. The antagonist produces a classical dose‐dependent rightward of the agonist response. (F ) Schild derivation of the data in E to derive a pA2 value (see UNIT ). View Image -
Figure 1.1.4 Pharmacological versus functional antagonism. (A ) GABAA receptor activation produces a signal (GABA release) which causes neuron B to produce a response. (B ) Pharmacological antagonism: blockade of the GABAA response at neuron B by a GABAA antagonist is a direct competitive effect. (C ) Functional antagonism: The same GABAA response on neuron B can be blocked in vivo by a nicotinic or dopaminergic antagonist via interactions with upstream events in a pathway. In the absence of any further data on the putative nicotinic or dopaminergic antagonist, they could be classified as GABAA antagonists. View Image
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