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A receptor can be defined loosely as ‘a molecule that recognizes specifically
a second small molecule whose binding brings about the regulation of a cellular process...in the unbound state a receptor
is functionally silent’. This definition states that a receptor binds specifically a particular ligand (e.g. bombesin
binds to bombesin receptors and not vanilloid receptors) but in reality selectivity is a more accurate definition as in some
cases high concentrations of ligands will bind to multiple receptor types. The caveat that in the unbound state a receptor
is silent holds true in most cases (particularly those encountered with current clinically useful drug-receptors) but an exception
can be used to explain inverse agonism. Receptors can be subdivided into four main classes: ligand-gated ion channels, tyrosine
kinase-coupled, intracellular steroid and G-protein-coupled (GPCR).
G protein-coupled receptors (GPCRs) form a large superfamily of membrane proteins
that modulate sensory perception, chemotaxis, neurotransmission, cell communication, and many other vital physiological events.
Characterized by their cell-surface localization and tissue-specificity, these protein receptors are the targets of 50-60%
of all existing medicines including well-known -blockers and anti-histamine therapeutics. It is generally accepted that a
better understanding of the function of these receptors and their structure will help in the design of drugs for the treatment
of GPCR-related diseases.
It is estimated that 340-400 pharmaceutically relevant GPCRs exist in the human
genome, although many have been classified as orphan receptors because their endogenous ligands have not yet been identified.
GPCR are generally classified into three groups: Rhodopsins, Secretins, and Metabolic Glutamate Receptors. The Rhodopsins
include hormone, neurotransmitter and light receptors. The Secretins include calcitonin, parathyroid hormone, and vasoactive
intestinal peptide. The Metabotropic Glutamate Receptors are similar in signature to calcium-sensing and GABA receptors.
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|
CHARACTER |
LGIC
(Ligand-Gated ion
Channel) |
TRK
(Tyrosine kinase couplled)
|
STEROID |
GPCR
(G-Protein Couplled
Receptor) |
|
LOCATION |
MEMBRANE |
MEMBRANE |
INTRACELLULAR |
MEMBRANE |
|
MAIN ACTION |
ION FLUX |
PHOSPHORYLATION |
GENE TRANSCRIPTION |
SECONDARY MESSANGER |
|
EXAMPLE/DRUG |
NICOTINIC/NMBD
NMDA/KETAMINE
(NMBD= Neuromuscular
blocking drugs)
(NMDA=
N-methyl-D-aspartate) |
INSULIN/INSULIN-GRWOTH-
FACTOR/EGF(Epidermal
growth factor) |
STEROID/THYROXINE
STEROID/OESTROGEN
|
OPIOID/MORPHINE
ADRENOCEPTORS/
ISOPRENALINE
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GPCR'S:
These receptors are located on the surface of cells where they have the
task to recognise specific molecules that signal to cells how to accommodate to the needs of an organ or a whole organism.
GPCRs
represent a very important class of drug targets. It is estimated that up to half of all currently marketed medicaments cause
their therapeutic effects via such receptors. Among the drugs acting on the central nervous system, the percentage is even
higher with estimates of 75% or more.
The total number of GPCRs in humans is estimated to lie between 500 and 2000.
Some of these GPCRs, such as the olfactory receptor involved in odour recognition, are rather unlikely to ever represent drug
targets. But even allowing for these kinds of receptors, there clearly is a large number of worthwhile drug targets in the
GPCRs family.
GPCR Groups:
Recent research is focussing on three groups of GPCRs, alpha-2 adrenergic,
somatostatin and RFamide receptors. The alpha-2 adrenoceptor has a role in learning and memory, mental states, blood
pressure and pain. The neurotransmitter somatostatin affects cognitive, locomotor, sensory and autonomic functions. Of the
RFamides, neuropeptide FF, another peptide neurotransmitter of the nervous system, exerts potent effects on pain sensation,
blood pressure and other autonomic functions, although a detailed understanding of its functions is still emerging.
GPCR's Sub-types:
Most GPCRs in humans are known to have several subtypes. For alpha-2 adrenoceptors,
three subtypes have been identified (alpha-2A, alpha-2B and alpha-2C), somatostatin receptors are known to exist as five different
subtypes (SSTR1-SSTR5) and NPFF receptors as two subtypes (NPFF1 and NPFF2). Receptor subtypes often differ in tissue distribution
and physiological role. Aiming at specific subtypes therefore offers the possibility to tackle particular diseases while leaving
functions mediated by other subtypes untouched.
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