Progress in developing cholecystokinin (CCK)/gastrin receptor ligands that have therapeutic potential
Introduction
The purpose of this article is to review progress in developing cholecystokinin (CCK)/gastrin receptor ligands that have therapeutic potential. To evaluate this question it is important to have some understanding of the role of these peptides and their receptors in normal physiology, human disease states (Table 1), the availability of possible therapeutic ligands (Table 2, Table 3) and the results of their use in humans either to evaluate normal physiology or to evaluate human disease states. Therefore, these areas will first be reviewed briefly. With this perspective, present and future potential therapeutic uses of these ligands can be considered.
This chapter will not include a detailed discussion of a number of related areas, which have been recently reviewed. Covered in such reviews (see references below) and not reviewed here include the chemistry of the development of CCK/gastrin receptor antagonists (see [1••, 2, 3••, 4, 5•, 6•, 7]) or agonists [2, 5•, 6•, 8••, 9] as well as a detailed discussion of the different chemical classes developed; detailed discussion of the biology of CCK [10, 11••, 12], gastrin [11••, 12, 13] or their receptors [11••] or detailed discussion of the studies that identified different potential disease states, especially in gastrointestinal (GI) disorders [2, 3••, 14•, 15•].
Section snippets
CCK/gastrin and their receptors and normal physiology
Although gastrin was described in 1905 and CCK in 1928, making them two of the oldest known hormones, it is primarily within the past 15 years that major advances have been made. With the development of selective agonists and antagonists (Table 2, Table 3) [1••, 2, 3••, 4, 5•, 6•, 7], their use in pharmacological, physiological and pathophysiological studies, and molecular characterization of the receptors and application of molecular techniques to studies, there have been major insights into
CCK/gastrin and their receptors and diseases (Table 1)
A large number of studies, primarily in animals, provide evidence that CCK1Rs are likely to be involved in various pancreatic disorders (acute and chronic pancreatitis), GI motility disorders (including functional dyspepsia, irritable bowel syndrome, chronic constipation, and gastroesophageal reflux disease), appetite/satiety regulation and disorders (obesity, bulimia, and anorexia nervosa), pain modulation, and possibly, regulation of tumor growth [3••, 14•, 15•].
Both animal and human studies
Selective CCK1R and CCK2R agonists and antagonists (Tables 2 and 3)
To explore the role of CCK1R or CCK2R in the above diseases or in physiological states selective ligands are needed, either selective agonists or antagonists. There have been numerous classes of CCK1R and CCK2R agonists [2, 5•, 6•, 8••, 9] and antagonists [1••, 2, 3••, 4, 5•, 6•, 41] described, and in many classes, highly selective members have been reported. Table 2 summarizes a number of CCK receptor agonists or antagonists that have been used in human diseases or physiological studies and
Use of CCK1R and CCK2R agonists and antagonists in humans (Table 2)
In human studies both relatively nonselective CCK1R and CCK2R agonists (CCK) and antagonists (proglumide, loxiglumide, and spiroglumide) as well as highly selective CCK1R and CCK2R agonists (CCK) and antagonists (Table 2) have been used to explore normal human physiology as well as various disease states [1••, 2, 3••, 8••, 14•, 15•]. At present no CCK1R or CCK2R antagonist is approved in the United States (US) for diagnosis or treatment of any disorder. Both CCK1 and CCK2R agonists have been in
Conclusions
The lack of established therapeutic uses of CCK receptor ligands, especially the antagonists, is not now because of a lack of selective agonists or antagonists. As shown in Table 2, Table 3 there are a number of different classes of compounds, both orally active and parenterally active that have high selectivity for either CCK1R or CCK2R. These are starting to be used to explore the proposed role of these receptors in different pathophysiological conditions. In some cases, such as recently
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgement
This work was partially supported by intramural funds from NIDDK, NIH.
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