| Item type: | Article | ||||||
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| Journal or Publication Title: | Bioorganic & Medicinal Chemistry | ||||||
| Publisher: | Elsevier | ||||||
| Volume: | 23 | ||||||
| Number of Issue or Book Chapter: | 14 | ||||||
| Page Range: | pp. 3970-3990 | ||||||
| Date: | 2015 | ||||||
| Additional Information (public): | Supplementary material available. Cf. http://www.sciencedirect.com/science/article/pii/S0968089615000188 | ||||||
| Institutions: | Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry II (Prof. Buschauer) | ||||||
| Identification Number: |
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| Keywords: | Muscarinic acetylcholine receptors; dibenzodiazepinones; antagonists; dimeric ligands; allosteric binding; AF-DX 384 | ||||||
| Dewey Decimal Classification: | 500 Science > 540 Chemistry & allied sciences 600 Technology > 615 Pharmacy | ||||||
| Status: | Published | ||||||
| Refereed: | Yes, this version has been refereed | ||||||
| Created at the University of Regensburg: | Partially | ||||||
| Item ID: | 30900 |
Abstract
A series of new dibenzodiazepinone-type muscarinic receptor ligands, including two homo-dimeric compounds, was prepared. Sixteen representative compounds were characterized in equilibrium binding studies with [3H]N-methylscopolamine ([3H]NMS) at the muscarinic receptor subtype M2, and seven selected compounds were additionally investigated at M1, M3, M4 and M5 with respect to receptor subtype ...
Abstract
A series of new dibenzodiazepinone-type muscarinic receptor ligands, including two homo-dimeric compounds, was prepared. Sixteen representative compounds were characterized in equilibrium binding studies with [3H]N-methylscopolamine ([3H]NMS) at the muscarinic receptor subtype M2, and seven selected compounds were additionally investigated at M1, M3, M4 and M5 with respect to receptor subtype selectivity. The side chain of the known M2 preferring muscarinic receptor antagonist DIBA was widely varied with respect to chain length and type of the basic group (amine, imidazole, guanidine and piperazine). Most of the structural changes were well tolerated with respect to muscarinic receptor binding, determined by displacement of [3H]NMS. Compounds investigated at all subtypes shared a similar selectivity profile, which can be summarized as M2 > M1 ≈ M4 > M3 ≈ M5 (46, 50, 57, 62-64) and M2 > M1 ≈ M4 > M3 > M5 (1, 58). The homo-dimeric dibenzodiazepinone derivatives UNSW-MK250 (63) and UNSW-MK262 (64) exhibited the highest M2 receptor affinities (pIC50 = 9.0 and 9.2, resp.). At the M2 receptor a steep curve slope of -2 was found for the dimeric ligand 63, which cannot be described according to the law of mass action, suggesting a more complex mechanism of binding. In addition to equilibrium binding studies, for selected ligands, we determined pEC50,diss, an estimate of affinity to the allosteric site of [3H]NMS occupied M2 receptors. Compounds 58 and 62-64 were capable of retarding [3H]NMS dissociation by a factor > 10 (Emax,diss > 92%), with highest potency (pEC50,diss = 5.56) residing in the dimeric compound 64. As the monomeric counterpart of 64 was 100 times less potent (62: pEC50,diss = 3.59), these data suggest that chemical dimerization of dibenzodiazepinone-type M receptor ligands can enhance allosteric binding.
Metadata last modified: 29 Sep 2021 07:40
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