Overview of Discussion- About Substance P (SP) Discovery of SP SP Receptor Functions mediated by SP Clinical significance of the SP-NK1R NK1 receptor antagonists

1. Mr. Vishal Balakrushna Jadhav
Assistant Professor (Pharmacology)
School of Pharmaceutical Sciences, Sandip University, Nashik
Substance P (SP)
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 About Substance P (SP)
 Discovery of SP
 SP Receptor
 Functions mediated by SP
 Clinical significance of the SP-NK1R
 NK1 receptor antagonists
Overview of Discussion

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 An undecapeptide member of the tachykinin neuropeptide family.
 A neuropeptide, acting as a neurotransmitter & as a neuromodulator.
 Produced from a polyprotein precursor after differential splicing of
the preprotachykinin A gene.
 Released from the terminals of specific sensory nerves.
 Found in the brain and spinal cord.
 Associated with inflammatory processes and pain.
About Substance P (SP)

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 The original discovery of Substance P (SP) (P standing for Preparation or
Powder) was in 1931 by Ulf von Euler and John H. Gaddum as a tissue
extract that caused intestinal contraction in vitro.
 Its tissue distribution and biologic actions were further investigated over
the following decades.
 The eleven-amino-acid structure of the peptide was determined by Chang,
et. al in 1971.
 In 1983, neurokinin A (NKA) (previously known as substance K or
neuromedin L, closely related to SP) was isolated from porcine (domestic
pig) spinal cord and was also found to stimulate intestinal contraction.
Discovery of SP

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 The endogenous receptor for substance P is neurokinin 1 receptor (NK1-
receptor, NK1R)→ belongs to the tachykinin receptor sub-family of GPCRs.
 Other neurokinin subtypes and neurokinin receptors that interact with SP
have been reported as well.
 Amino acid residues present in the extracellular loops and transmembrane
regions of NK1R are responsible for the binding of SP and its antagonists.
 Substance P and the NK1 receptor are widely distributed in the brain and
are found in brain regions that are specific to regulating emotion
(hypothalamus, amygdala, and the periaqueductal gray).
 Cytoplasmic membranes of many cell types (neurons, glia, endothelia of
capillaries and lymphatics, fibroblasts, stem cells, white blood cells) also
expresses Nk1R.
 They are found in close association with serotonin (5-HT) and neurons
containing norepinephrine that are targeted by the currently used
antidepressant drugs.
 Cytokines and neurotropic factors can induce NK-1, and SP can induce the
cytokines that are capable of inducing NK-1 transcription factors.
SP Receptor

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 Substance P is a key first responder to most noxious/extreme stimuli
(stressors).
 SP is thus regarded as an immediate defense, stress-repair, survival system.
 The SP molecule which is rapidly inactivated (or at times further activated
by peptidases) is rapidly released repetitively and chronically, as necessary,
in the presence of a stressor.
 The functions mediated by SP includes-
a) Vasodilation
b) Inflammation
c) Pain
d) Mood, anxiety, learning
e) Vomiting, and
f) Cell growth, proliferation, angiogenesis, and migration.
Functions mediated by SP

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a) Vasodilation
 SP is a potent vasodilator→ vasodilation is dependent on nitric
oxide release.
 Also involved in the axon reflex-mediated vasodilation to local heating,
and wheal and flare reaction.
 It has been shown that vasodilation to SP is dependent on the NK1 receptor
located on the endothelium.
 In contrast to other neuropeptides, substance P-induced vasodilation has
been found to decline during continuous infusion.
b) Inflammation
 Cytokines and neurotropic factors can induce NK-1, and SP can induce the
cytokines that are capable of inducing NK-1 transcription factors.
 SP and other sensory neuropeptides can be released from the peripheral
terminals of sensory nerve fibers in the skin, muscle, and joints. This release
thereby mediates neurogenic inflammation, which is a local inflammatory
response to certain types of infection or injury.

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c) Pain
 Preclinical data support that SP is an important element in pain perception.
 The sensory function of SP is related to the transmission of pain
information into the central nervous system.
 SP coexists with the excitatory neurotransmitter glutamate in primary
afferents that respond to painful stimulation.
 SP and other sensory neuropeptides can be released from the peripheral
terminals of sensory nerve fibers in the skin, muscle, and joints. It is
proposed that this release is involved in neurogenic inflammation, which is
a local inflammatory response to certain types of infection or injury.
d) Mood, anxiety, learning
 SP has been associated with the regulation of mood
disorders, anxiety, stress, reinforcement, neurogenesis, respiratory
rhythm, neurotoxicity, pain, and nociception.

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e) Vomiting
 Area Postrema, the vomiting center in the medulla contains high
concentrations of SP and its receptor, in addition to other neurotransmitters
such as choline, histamine, dopamine, serotonin, and opioids.
 Their activation stimulates the vomiting reflex.
f) Cell growth, proliferation, angiogenesis, and migration
 SP has been known to stimulate cell growth in normal and cancer cell line
cultures.
 SP could promote wound healing of non-healing ulcers in humans.
 SP and its induced cytokines promote multiplication of cells required for
repair or replacement, growth of new blood vessels.

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1) Quantification in disease
 Elevation of serum, plasma, or tissue SP and/or its receptor (NK1R) has
been associated with many diseases such as sickle cell crisis, inflammatory
bowel disease, major depression and related disorders, fibromyalgia,
rheumatoid arthritis, and infections such as HIV/AIDS and respiratory
syncytial virus as well as in cancer.
 However, SP concentrations cannot yet be used to diagnose disease
clinically or test disease severity. It is not yet known whether changes in
concentration of SP or density of its receptors is the cause of any given
disease, or an effect.
2) Chemotherapy induced nausea and vomiting
 SP is released when toxins or poisons come into contact with a range of
receptors in the chemoreceptor trigger zone, located in the floor of the
fourth ventricle of the brain, the area postrema.
 Presumably, SP is released in or around the nucleus tractus solitarius
(NTS) on integrated activity of dopamine, serotonin, opioid, and/
or acetylcholine.
Clinical significance of the SP-NK1R

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Neurokinin 1 (NK1) antagonists (-pitants) are a novel class of medications that
possesses unique antidepressant, anxiolytic and antiemetic properties.
NK-1 antagonists increase the efficacy of 5-HT3 antagonists to prevent nausea
and vomiting.
The discovery of neurokinin 1 (NK1) receptor antagonists was a turning point
in preventing nausea and vomiting associated with cancer chemotherapy.
Chemotherapy-induced emesis appears to consist of acute and delayed
phases. The acute phase emesis responds to 5-HT3 antagonists (like
ondansetron) while the delayed phase remains difficult to control.
The discovery and development of NK1 receptor antagonists (e.g. aprepitant,
casopitant, netupitant and rolapitant) have elicited antiemetic effect in
both acute and especially in delayed phases of emesis.
Rolapitant has a significantly longer half-life of 160 hours and was approved
by the US FDA in 2015.
The first registered clinical use of NK1 receptor antagonists was the treatment
of emesis associated with cancer chemotherapy.
NK1 receptor antagonists

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