DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1108
SECTION V
HORMONES AND HORMONE ANTAGONISTS
Ala Gly Cys Lys Asn Phe Phe
SST-14
D-Phe
S
S
Cys
Thr(ol) Cys Thr
Octreotide
D-Phe
Cys
S
S
Cys
S
S
Phe
Trp(NH 2 ) Cys Val
Vapreotide
Tyr
Ala(N-CH 3 )
Phe
Val
Tyr
Seglitide
Ser
D-Trp
Lys
D-Trp
Lys
D-Trp
Lys
D-Nal
Thr Phe Thr
Cys
Tyr
Thr Cys Val
Lanreotide
APro
Phe
PGly
Trp
Lys
D-Trp
Lys
Somatostatin is synthesized as a 92–amino acid
precursor and processed by proteolytic cleavage to generate
two peptides: SST-28 and SST-14. SST-14 consists
of the carboxy-terminal 14 amino acids of SST-28,
which form an intrapeptide disulfide bond (Figure 38–3).
SST exerts its effects by binding to and activating a
family of five related GPCRs that signal through G i
to
inhibit cyclic AMP accumulation and to activate K +
channels and protein phosphotyrosine phosphatases.
Each of the SST receptor subtypes (abbreviated SSTRs) binds
SST with nanomolar affinity; whereas receptor types 1-4 (SSTR1-4)
bind the two SSTs with approximately equal affinity, type 5 (SSTR5)
has a 10- to 15-fold greater affinity for SST-28. SSTR2 and SSTR5
are the most important for regulation of GH secretion, and recent
studies suggest that these two SSTRs form functional heterodimers
S
S
D-Trp
Lys
BTyr
Pasireotide
Figure 38–3. Structures of somatostatin-14 and selected synthetic
analogs. The amino acid sequence of somatostatin (SST)-14
is shown. Residues that play key roles in receptor binding, as
discussed in the text, are shown in red. Also shown are the structures
of the two clinically available synthetic analogs of somatostatin,
octreotide and lanreotide, and three other analogs that
have been used in clinical trials, seglitide, vapreotide, and
pasireotide. APro, [(2-aminoethyl) aminocarboxyl oxy]-Lproline;
D-Nal, (3-(2-napthyl)-D-alanyl; PGly, phenylglycine;
BTyr, benzyltyrosine.
with distinctive signaling behavior (Grant et al., 2008). SST exerts
direct effects on somatotropes in the pituitary and indirect effects
mediated via GHRH neurons in the arcuate nucleus. As discussed
later, SST analogs play a key role in the pharmacotherapy of syndromes
of GH excess and certain cancers.
Ghrelin, a 28-amino acid peptide that is octanoylated
at Ser3, also stimulates GH secretion. Ghrelin is
synthesized predominantly in endocrine cells in the
fundus of the stomach but also is produced at lower
levels at a number of other sites. Both fasting and
hypoglycemia stimulate circulating ghrelin levels.
Ghrelin acts primarily through a GPCR called the GH secretagogue
receptor. Although the interaction of ghrelin with this receptor
directly stimulates GH release by isolated somatotropes, the
major action on GH secretion apparently is through actions on the
GHRH neurons in the arcuate nucleus. Apart from its effects on GH
secretion, ghrelin also stimulates appetite and increases food intake,
apparently by central actions on NPY and agouti-related peptide
neurons in the hypothalamus. Thus, ghrelin and its receptor act in a
complex manner to integrate the functions of the GI tract, the hypothalamus,
and the anterior pituitary (Ghigo et al., 2005). Peptide and
nonpeptide agonists (termed GH secretagogues) and antagonists of
the GH secretagogue receptor are undergoing evaluation as possible
modulators of neuroendocrine function.
Several neurotransmitters, drugs, metabolites,
and other stimuli modulate the release of GHRH
and/or SST and thereby affect GH secretion. DA, 5-HT,
and α 2
adrenergic receptor agonists stimulate GH
release, as do hypoglycemia, exercise, stress, emotional
excitement, and ingestion of protein-rich meals. In contrast,
β adrenergic receptor agonists, free fatty acids,
IGF-1, and GH itself inhibit release, as does the administration
of glucose to normal subjects in an oral glucosetolerance
test.
Many of the physiological factors that influence
prolactin secretion also affect GH secretion. Thus sleep,
stress, hypoglycemia, exercise, and estrogen increase
the secretion of both hormones.
Prolactin is unique among the anterior pituitary
hormones in that hypothalamic regulation of its secretion
is predominantly inhibitory. The major regulator
of prolactin secretion is DA, which is released by
tuberoinfundibular neurons and interacts with the D 2
receptor, a GPCR on lactotropes, to inhibit prolactin
secretion (Figure 38–4). Recent reports have suggested
that the D 2
receptor and the SST 2
receptor can form
heterodimers (Baragli et al., 2007), which may have
implications for therapy (see following discussion).
A number of putative prolactin-releasing factors have
been described, including TRH, VIP, prolactin-releasing peptide,
and PACAP, but their physiological roles are unclear. Under certain