Page 328 - Basic _ Clinical Pharmacology ( PDFDrive )

314 SECTION IV Drugs with Important Actions on Smooth Muscle

to be approved for the prevention of chemotherapy-induced and to cross the blood-brain barrier. However, a series of analogs of
postoperative nausea and vomiting is aprepitant (see Chapter 62). NT(8-13) that exert antipsychotic-like activity in animal stud-
Fosaprepitant is a prodrug that is converted to aprepitant after ies has been developed. These agonists include NT69L, which
intravenous administration and may be a useful parenteral alterna- binds with high affinity to NTR and NTR ; and NT79, which
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tive to oral aprepitant. preferentially binds to NTR . Another agonist, PD149163, has
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The substance P-NK system has also been implicated in improved metabolic stability.
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cancer. Substance P and NK receptors are present in a variety In addition to their possible role as antipsychotic drugs, these
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of tumor cells, and NK receptor antagonists exert an antitumor agonists may be useful in the treatment of pain, psychostimulant
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action. Thus, drugs such as aprepitant may have potential as anti- abuse, and Parkinson’s disease. Potential adverse effects include
cancer agents. hypothermia and hypotension. Development of tolerance to some
of the effects of the agonists may occur.
NT receptors can be blocked with the nonpeptide antago-
■ NEUROTENSIN nists SR142948A and meclinertant (SR48692). SR142948A is a
potent antagonist of the hypothermia and analgesia produced by
Neurotensin (NT) is a tridecapeptide that was first isolated from centrally administered NT. It also blocks the cardiovascular effects
the central nervous system but subsequently was found to be pres- of systemic NT.
ent in the gastrointestinal tract. It is also present in the circulation
and in several organs including the heart, lungs, liver, pancreas,
and spleen. ■ CALCITONIN GENE-RELATED
NT is synthesized as part of a larger precursor that also con- PEPTIDE
tains neuromedin N, a six-amino-acid NT-like peptide. In the
brain, processing of the precursor leads primarily to the forma- Calcitonin gene-related peptide (CGRP) is a member of the
tion of NT and neuromedin N; these are released together from calcitonin family of peptides, which also includes calcitonin,
nerve endings. In the gut, processing leads mainly to the forma- adrenomedullin, and amylin. CGRP consists of 37 amino
tion of NT and a larger peptide that contains the neuromedin acids. In humans, CGRP exists in two forms termed α-CGRP
N sequence at the carboxyl terminal. Both peptides are secreted and β-CGRP, which are derived from separate genes and differ
into the circulation after ingestion of food. Most of the activity of by three amino acids but exhibit similar biological activity.
NT is mediated by the last six amino acids, NT(8-13). Like calcitonin, CGRP is present in large quantities in the
Like many other neuropeptides, NT serves a dual function C cells of the thyroid gland. It is also distributed widely in
as a neurotransmitter or neuromodulator in the central nervous the central and peripheral nervous systems, cardiovascular and
system and as a local hormone in the periphery. When adminis- respiratory systems, and gastrointestinal tract. In the cardio-
tered centrally, NT exerts potent effects including hypothermia, vascular system, CGRP-containing neuronal fibers are more
antinociception, and modulation of dopamine and glutamate abundant around arteries than around veins and in atria than
neurotransmission. When administered into the peripheral circu- in ventricles. CGRP fibers are associated with most smooth
lation, it causes vasodilation, hypotension, tachycardia, increased muscles of the gastrointestinal tract. CGRP is found with
vascular permeability, increased secretion of several anterior substance P (see above) in some of these regions and with
pituitary hormones, hyperglycemia, inhibition of gastric acid and acetylcholine in others.
pepsin secretion, and inhibition of gastric motility. It also exerts When CGRP is injected into the central nervous system, it
effects on the immune system. produces a variety of effects, including hypertension and sup-
In the central nervous system, there are close associations pression of feeding. When injected into the systemic circulation,
between NT and dopamine systems, and NT may be involved the peptide causes hypotension and tachycardia. The hypoten-
in clinical disorders involving dopamine pathways such as sive action of CGRP results from the potent vasodilator action
schizophrenia, Parkinson’s disease, and drug abuse. Consistent of the peptide; indeed, CGRP is the most potent vasodilator yet
with this, it has been shown that central administration of NT discovered. It dilates multiple vascular beds, but the coronary
produces effects in rodents similar to those produced by antipsy- circulation is particularly sensitive. The vasodilation is mediated
chotic drugs. via a nonendothelial mechanism through activation of adenylyl
The effects of NT are mediated by three subtypes of NT recep- cyclase.
, NTR , and NTR , also known as NTS , The actions of CGRP are mediated via a single receptor type.
tors, designated NTR 1 2 3 1
NTS , and NTS . NTR and NTR receptors belong to the G This heterodimeric receptor consists of the G protein-coupled
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q
2
3
2
protein-coupled superfamily. NTR has a higher affinity for NT calcitonin receptor-like receptor (CLR) combined with the recep-
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than NTR and is the major mediator of the diverse effects of tor activity-modifying protein RAMP1.
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NT. The NTR receptor is a single-transmembrane protein that is Peptide and nonpeptide antagonists of the CGRP receptor have
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structurally unrelated to NTR or NTR . It belongs to a family of been developed. CGRP 8-37 has been used extensively to investigate
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2
sorting proteins and is therefore known as NTR /sortilin. the actions of CGRP but displays affinity for other related recep-
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The potential use of NT as an antipsychotic agent has been tors including those for adrenomedullin (see below). Nonpeptide
hampered by its rapid degradation in the circulation and inability CGRP receptor antagonists target the interface between CLR and