Melanocortin 2 receptor antagonists in canine pituitary-dependent hypercortisolism: in vitro studies
Open accessAbstract
Canine hypercortisolism is most often caused by an ACTH-secreting pituitary adenoma (pituitary-dependent hypercortisolism; PDH). An interesting target for a selective medical treatment of PDH would be the receptor for ACTH: the melanocortin 2 receptor (MC2R). In this study we investigated whether two peptide compounds, BIM-22776 (#776) and BIM-22A299 (#299), are effective MC2R antagonists in vitro. Their effects on cortisol production and mRNA expression of steroidogenic enzymes, MC2R and melanocortin 2 receptor accessory protein (MRAP) were evaluated in primary adrenocortical cell cultures (n = 8) of normal canine adrenal glands. Cortisol production stimulated by 50 nM ACTH was dose-dependently inhibited by #299 (inhibition 90.7 ± 2.3% at 5 μM) and by #776 (inhibition 38.0 ± 5.2% at 5 μM). The ACTH-stimulated mRNA expression of steroidogenic enzymes, MC2R and MRAP was significantly inhibited by both compounds, but most potently by #299. These results indicate that canine primary cell culture is a valuable in vitro system to test MC2R antagonists, and that these compounds, but especially #299, are effective MC2R antagonists in vitro. To determine its efficacy in vivo, further studies are warranted. Antagonism of the MC2R is a promising potential treatment approach in canine PDH.
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A single-dose, fixed-sequence study of 8 women given 300 or 600 mg of the CRHR1 antagonist NBI77860 at 2200 showed significant reductions in ACTH and 17OHP over the ensuing 16 hours relative to a control period during which glucocorticoid treatment was withheld.
“A single-dose, fixed-sequence study of 8 women given 300 or 600 mg of the CRHR1 antagonist NBI77860 at 2200 (10 PM) showed significant reductions in ACTH and 17OHP over the ensuing 16 hours relative to a control period during which glucocorticoid treatment was withheld (498).”
From Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management (2022) · cites this paper as [498]
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Cites
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“However, since the other melanocortin receptors have a variety of functions in other tissue types, inadvertently antagonizing or agonizing these receptors could result in many unwanted side-effects (Clark et al. 2016).”
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Cited by
Sorted by citations
Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management
Claahsen - van der Grinten, H. L., Speiser, P. W., Ahmed, S. F., Arlt, W., Auchus, R. J., Falhammar, H., Flück, C. E., Guasti, L., Huebner, A., Kortmann, B. B. M., et al. (2022) · Endocrine Reviews · doi:10.1210/endrev/bnab016 · Cited by 556 · see citing works
Management challenges and therapeutic advances in congenital adrenal hyperplasia
Mallappa, A., & Merke, D. P. (2022) · Nature Reviews Endocrinology · doi:10.1038/s41574-022-00655-w · Cited by 113 · see citing works
- Authors
- Sanders, K., Mol, J. A., Kooistra, H. S., & Galac, S.
- Affiliations
- Utrecht University (NL)
- Corresponding author
- Sanders, Karin
- Venue
- Veterinary Research Communications
- Published
- 2018-09-05
- Volume
- 42
- Issue
- 4
- Pages
- 283-288
- ISSN
- 0165-7380 (ISSN-L)
- 1573-7446
- PMC
- PMC6244543
- OpenAlex
- W2890516623
- Cited by
- 13
- References
- 3
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2023: 2 · 2022: 5 · 2021: 1 · 2019: 1
- FWCI
- 0.73
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Veterinary Research Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Funders
- Morris Animal Foundation (D15CA-052)
- Topics
- Health Sciences › Veterinary › Small Animals › Veterinary Medicine and Surgery
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pituitary Gland Disorders and Treatments
- Keywords
- Cushing's disease, cortisol production, steroidogenic enzymes, MRAP, adrenocortical cells
- MeSH terms
- Adrenal Cortex, Animals, Cells, Cultured, Dog Diseases, Dogs, Female, Hydrocortisone, Male, Receptor, Melanocortin, Type 2, Pituitary ACTH Hypersecretion, Real-Time Polymerase Chain Reaction, In Vitro Techniques
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