calculations. Theoretical pharmacophore analyses using such calculations indicate that
CRF-1 ligands should possess a hydrogen bond acceptor in a core aromatic heterocycle
that is flanked by a branched alkyl group and a 2,4-disubstituted aromatic substituent.
The core aromatic heterocycle may be six-membered or even five-membered, such as
thiazoles, pyrazoles, or imidazoles.
As mentioned, CRF antagonists can be employed in the treatment of a wide variety
of disorders. One particularly important area is in the treatment of irritable bowel
syndrome[IBS], a disorder characterized by abdominal discomfort or pain associated
with a change in the frequency of stool passage and a change in the form of the stool.
CRF-1 mediates the increase in colonic motility, whilst CRF-2 mediates the associated
delay in colonic emptying; accordingly, CRF-1 and CRF-2 antagonists may provide
novel therapeutic approaches for IBS. (It is highly significant that neurologically active
agents are used in the treatment of gastrointestinal disorders. The gut has an extensive
NEUROTRANSMITTERS AND THEIR RECEPTORS 289
Table 4.3Neuroactive Brain Peptides
Class Peptide
Gastrointestinal peptides Cholecystokinin
Bombesin
Gastrin
Glucagon
Insulin
Leucine-enkephalin
Methionine-enkephalin
Motilin
Neurotensin
Secretin
Somatostatin
Substance P
Thyrotropin-releasing hormone
Vasoconstrictive intestinal polypeptide
Hypothalamic releasing hormone Corticotropin-releasing hormone
Gonadotropin-releasing hormone
Growth hormone-releasing hormone
Somatostatin
Thyrotropin-releasing hormone
Neurohypophyseal hormones Oxytocin
Vasopressin
Pituitary peptides Adrenocorticotropic hormone
α-Melanocyte-stimulating hormone
β-Endorphin
Growth hormone
Luteinizing hormone
Prolactin
Thyrotropin
Other Angiotensin II
Bradykinin
Calcitonin
Galanin
Neuropeptide Y
Substance K