manipulation of the cysteines in SS analogs. When Cys^3 is replaced by its D-enantiomer,
insulin release is preferentially inhibited; when the L-Cys^14 is replaced, an increase
in the inhibition of glucagon secretion occurs. When the C-terminal cysteine forms a
lactam with the N-terminal of Ala^1 , resulting in cyclo-SS, growth-hormone repression
becomes enhanced.
Of the various somatostatin analogs developed, octreotide (5.76) has been the most
clinically effective. Octreotide is 45 times more potent than somatostatin in inhibiting
GH release but decreases insulin release by only a factor of 2. It is useful in the treatment
of acromegaly and in the treatment of hormone-producing tumors such as gastrinomas or
glucagonomas. Radiolabeled octreotide has been used to localize neuroendocrine
tumors that express somatostatin receptors. Gallstones will occur in 30% of patients
receiving octreotide for more than 6 months.
5.15.2.6 Corticotropin Releasing Factor
Corticotropin releasing factor (CRF) is a neurohormone that has attracted considerable
attention in the area of drug design. CRF exerts its actions by interacting with one of
two subtypes of G-protein-coupled receptors (CRF 1 , CRF 2 ), each being encoded by
separate genes (cDNA encoding a third receptor has been isolated from catfish pitu-
itary). All of these receptors possess seven putative transmembrane domains and are
positively coupled to adenylate cyclase. Ongoing research is endeavoring to develop
receptor-specific agents for four CRF receptors: CRF 1 , CRF 2 α, CRF 2 β, and CRF 2 γ.
Aiding this design process is the fact that the primary amino acid sequences of these
various receptors are known. For example, the CRF 2 αreceptor has 411 amino acids and
has 71% sequence homology with the CRF 1 receptor protein.
Over the past decade, studies with CRF peptide analogs have provided invaluable
structure–activity relationship information. Deletion of residues from the N-terminal of
CRF reduces potency but maintains efficacy. However, when leucine 8 is deleted, the
resulting analogs start to behave as antagonists rather than agonists. Binding affinity of
the peptide for its receptor(s) can be modified by alterations to residues 8–32. Such
information is useful in the drug design strategy.
Since peptides have limited utility as drugs, the design and synthesis of low molecular
weight non-peptidic ligands for CRF receptors is an active research area. These drug
design and discovery programs employ peptidomimetic strategies for obtaining non-
peptidic drugs from peptides (discussed in chapter 3) and combinatorial chemistry libraries
with high throughput screening (also discussed in chapter 3). These non-peptide ligands
tend to have a core aromatic heterocycle with appended hydrogen bonding acceptors and
other functional groups with binding potential appended to it. Five-membered (pyrazoles,
HORMONES AND THEIR RECEPTORS 345