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  • The eradication of agonist activity

    2021-11-26

    The eradication of agonist activity in compound was also confirmed in the ex vivo growth hormone (GH) release experiment conducted in isolated primary rat pituitary Deforolimus sale as shown in . Compound did not produce any noticeable GH secretion at up to 10μM concentration. It could also antagonize the stimulating effect of ghrelin (0.2μM) on GH release from rat pituitary cells (IC=93nM), as shown in . In summary, we optimized a series of piperazine-bisamide based GHSR inhibitors for potency and removed the partial agonist activity seen with the early lead compounds in the IP assays. The efforts led to the discovery of tool compound , which was featured with high potency, satisfactory PK profile, and sufficient CNS exposure in mdr1a knockout mice. The compound was also confirmed to be an antagonist in the ex vivo study of GH release from isolated primary rat pituitary cells. Compound was proved to be a useful tool for evaluation in in vivo proof-of-concept studies in mouse, and the results will be published in due course. Acknowledgments
    Introduction Ghrelin, a peptide hormone that is principally released from the stomach, has been identified as an endogenous ligand for the growth hormone (GH) secretagogue receptor (GHSR-1a), which is expressed in the pituitary gland and the hypothalamus mediating its potent GH secreting effects [9]. However, ghrelin and its receptor are also expressed in a variety of other tissues, and multiple functions of this peptide – independent of GH secretion – have been described [5], [10]. Increasing evidence supports a role of the ghrelin system in the direct regulation of cardiovascular function: Iglesias et al. [7] demonstrated not only the presence of ghrelin receptors in the heart and vascular structures, but also that cultured cardiomyocytes are able to synthesize ghrelin, suggesting that ghrelin may have a paracrine/autocrine function in cardiac muscle. Ghrelin protects from heart failure induced by myocardial infarction or ischemia-reperfusion injury in vitro, and a few preliminary data indicate that administration of ghrelin to patients with chronic heart failure (CHF) improves cardiac function and decreases systemic vascular resistance [3], [13], [23]. Given the fact that both ghrelin and GHSR-1a are expressed in the myocardium itself [8], [17], one may speculate that the ghrelin system may have direct autocrine or paracrine impact on cardiac function, independent of the hypothalamic GH axis. However, direct intrinsic influences of ghrelin on the myocardium have not yet been differentiated from secondary effects (resulting from GH release and vasomotor action) and thus, the role of the ghrelin signaling system in the networks regulating cardiac function remains elusive.
    Methods
    Results
    Discussion Emerging evidence indicates that ghrelin and its receptor GHSR-1a are present in heart, and administration of ghrelin has been shown to exert beneficial cardiovascular effects in both animal models [1], [4], [11], [14], [24] and in humans [3], [13], [15]. In order to estimate the potential of ghrelin as a target for diagnosis and/or treatment of CHF, it is indispensable to differentiate its direct intrinsic (paracrine/autocrine) myocardial effects from the secondary effects resulting from growth hormone release and vasomotor action. Thus, the expression pattern of ghrelin and its receptor in healthy hearts and the changes occurring in CHF might be of major interest. Our results strongly promote the thesis that the ghrelin-system indeed is primarily involved in myocardial processes as myocardial ghrelin expression is directly associated with myocardial function: an impaired myocardium exhibits an impaired ghrelin production. Taking into account the performance-enhancing effects of ghrelin on myocardial function shown by others [6], [12], [13], [20], the reduced ghrelin expression in CHF might reflect maladaptive changes of the failing heart which might further enhance the pathologic processes. The detected increase in GHSR-1a expression – on the other hand – might be regarded as a consecutive mechanism to compensate for the decreased hormone production. The impaired cardiac ghrelin signaling might not only have local but also systemic effects: Lund et al. [12] documented elevated circulating levels of ghrelin in patients presenting with HF independently of their body mass index (in contrast to the data of Nagaya et al. [16], who demonstrated elevated levels of ghrelin only in cachectic patients with HF). Furthermore, the authors described that resistance to the appetite stimulating effects of ghrelin occurs in HF and resolves post-heart transplantation. In the light of our study, these findings may indicate that ghrelin levels in HF may be elevated not only as a consequence of cachexia, but also in response to cardiac dysfunction itself. Low cardiac output with low cardiac ghrelin production may send out so far unknown signals leading to a compensatory increase of systemic ghrelin production. The simultaneously occurring ghrelin resistance indicates that additional factors such as growth hormone resistance or catabolic/anabolic imbalance and/or inadequate caloric intake may also play an important role in the regulation of these complex networks.