Keller, Max and Traenkle, Christian and She, Xueke and Pegoli, Andrea and Bernhardt, Guenther and Buschauer, Armin and Read, Roger W. (2015) M-2 Subtype preferring dibenzodiazepinone-type muscarinic receptor ligands: Effect of chemical homo-dimerization on orthosteric (and allosteric?) binding. BIOORGANIC & MEDICINAL CHEMISTRY, 23 (14). pp. 3970-3990. ISSN 0968-0896, 1464-3391
Full text not available from this repository. (Request a copy)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 [H-3]N-methylscopolamine ([H-3]NMS) at the muscarinic receptor subtype M-2, and seven selected compounds were additionally investigated at M-1, M-3, M-4 and M-5 with respect to receptor subtype selectivity. The side chain of the known M-2 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 [H-3]NMS. Compounds investigated at all subtypes shared a similar selectivity profile, which can be summarized as M-2 > M-1 approximate to M-4 > M-3 approximate to M-5 (46, 50, 57, 62-64) and M-2 > M-1 approximate to M-4 > M-3 > M-5 (1, 58). The homo-dimeric dibenzodiazepinone derivatives UNSW-MK250 (63) and UNSW-MK262 (64) exhibited the highest M-2 receptor affinities (pIC(50) = 9.0 and 9.2, respectively). At the M-2 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 pEC(50,diss), an estimate of affinity to the allosteric site of M-2 receptors occupied with [H-3]NMS. Compounds 58 and 62-64 were capable of retarding [H-3]NMS dissociation by a factor > 10 (E-max,E-diss >92%), with highest potency (pEC(50,diss) = 5.56) residing in the dimeric compound 64. As the monomeric counterpart of 64 was 100 times less potent (62: pEC(50),(diss) = 3.59), these data suggest that chemical dimerization of dibenzodiazepinone-type M receptor ligands can enhance allosteric binding. (C) 2015 Elsevier Ltd. All rights reserved.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | AF-DX 384; AUTORADIOGRAPHIC DISTRIBUTION; ANTAGONIST TRIPITRAMINE; ALZHEIMERS-DISEASE; COMMON SITE; RAT-BRAIN; MODULATORS; AGONISTS; M2; ACETYLCHOLINE; Muscarinic acetylcholine receptors; Dibenzodiazepinones; Antagonists; Dimeric ligands; Allosteric binding; AF-DX 384 |
| Subjects: | 500 Science > 540 Chemistry & allied sciences |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry II (Prof. Buschauer) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 05 Jul 2019 13:22 |
| Last Modified: | 05 Jul 2019 13:22 |
| URI: | https://pred.uni-regensburg.de/id/eprint/5208 |
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