High-throughput screening of Tranzyme Pharma's proprietary macrocycle library using the aequorin Ca2+-bioluminescence assay against the human ghrelin receptor (GRLN) led to the discovery of novel agonists against this G-protein coupled receptor. Early hits such as 1 (Ki=86 nM, EC50=134 nM) though potent in vitro displayed poor pharmacokinetic properties that required optimization. While such macrocycles are not fully rule-of-five compliant, principally due to their molecular weight and clogP, optimization of their pharmacokinetic properties proved feasible largely through conformational rigidification. Extensive SAR led to the identification of 2 (Ki=16 nM, EC50=29 nM), also known as ulimorelin or TZP-101, which has progressed to phase III human clinical trials for the treatment of postoperative ileus. X-ray structure and detailed NMR studies indicated a rigid peptidomimetic portion in 2 that is best defined as a nonideal type-I' β-turn. Compound 2 is 24% orally bioavailable in both rats and monkeys. Despite its potency, in vitro and in gastric emptying studies, 2 did not induce growth hormone (GH) release in rats, thus demarcating the GH versus GI pharmacology of GRLN.

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Imaging biomarkers are frequently proposed as endpoints for clinical trials targeting brain amyloidosis in Alzheimer's disease (AD); however, the specific impact of amyloid-β (Aβ) aggregation on biomarker abnormalities remains elusive in AD. Using the McGill-R-Thy1-APP transgenic rat as a model of selective Aβ pathology, we characterized the longitudinal progression of abnormalities in biomarkers commonly used in AD research. Middle-aged (9–11 months) transgenic animals (both male and female) displayed mild spatial memory impairments and disrupted cingulate network connectivity measured by resting-state fMRI, even in the absence of hypometabolism (measured with PET [18F]FDG) or detectable fibrillary amyloidosis (measured with PET [18F]NAV4694). At more advanced ages (16–19 months), cognitive deficits progressed in conjunction with resting connectivity abnormalities; furthermore, hypometabolism, Aβ plaque accumulation, reduction of CSF Aβ1-42 concentrations, and hippocampal atrophy (structural MRI) were detectable at this stage. The present results emphasize the early impact of Aβ on brain connectivity and support a framework in which persistent Aβ aggregation itself is sufficient to impose memory circuits dysfunction, which propagates to adjacent brain networks at later stages.SIGNIFICANCE STATEMENT The present study proposes a “back translation” of the Alzheimer pathological cascade concept from human to animals. We used the same set of Alzheimer imaging biomarkers typically used in large human cohorts and assessed their progression over time in a transgenic rat model, which allows for a finer spatial resolution not attainable with mice. Using this translational platform, we demonstrated that amyloid-β pathology recapitulates an Alzheimer-like profile of biomarker abnormalities even in the absence of other hallmarks of the disease such as neurofibrillary tangles and widespread neuronal losses.

Hippocampal shrinkage is a commonly found neuroanatomical change in stress-related mood disorders such as depression and post-traumatic stress disorders (PTSD). Since the onset and severity of these disorders have been found to be closely related to stressful life events, and as stress alone has been shown to reduce hippocampal volume in animal studies, vulnerability to mood disorders may be related to a susceptibility to stress-induced hippocampal shrinkage. However, a smaller hippocampal volume before stress exposure has also been suggested to confer vulnerability of stressed individuals to PTSD or depression. In this study, we examined the contribution of either innate hippocampal volume differences or hippocampal susceptibility to stress-induced shrinkage to the formation of stress-related psychopathology using longitudinal MRI measurements of hippocampal volume in inbred C57 mice before and after chronic social defeat stress. We found that only half of the stressed C57 mice were susceptible to stress and developed psychopathological behaviors such as social avoidance. The other half was resilient to stress and exhibited no social avoidance. Before exposure to stress, we observed a positive correlation between hippocampal volume and social avoidance. After chronic social defeat stress, we found significant increases in left hippocampal volume in resilient and nonstressed control mice. Intriguingly, this increase in hippocampal volume was not found in susceptible mice, suggesting an arrestment of hippocampal growth in these mice. Our findings suggest that both a susceptibility to stress-induced hippocampal volume changes and a larger hippocampus before stress exposure confer vulnerability to psychopathology after chronic stress.