In the present article, the M1mAChR bitopic agonist 1-[3-(4-butylpiperidin-1-yl)propyl]-1,2,3,4-tetrahydroquinolin-2-one (77-LH-28-1, 1) has been demonstrated to show unexpected D4R selectivity over D2R and D3R and to behave as a D4R antagonist. To better understand the structural features required for the selective interaction with the D4R and to obtain compounds unable to activate mAChRs, the aliphatic butyl chain and the piperidine nucleus of 1 were modified, affording compounds 2-14. The 4-benzylpiperidine 9 and the 4-phenylpiperazine 12 showed high D4R affinity and selectivity not only over the other D2-like subtypes, but also over M1-M5mAChRs. Derivative 12 was also highly selective over some selected off-targets. This compound showed biased behavior, potently and partially activating Giprotein and inhibiting β-arrestin2 recruitment in functional studies. Pharmacokinetic studies demonstrated that it was characterized by a relevant brain penetration. Therefore, 12 might be a useful tool to better clarify the role played by D4R in disorders in which this subtype is involved.

1-[3-(4-Butylpiperidin-1-yl)propyl]-1,2,3,4-tetrahydroquinolin-2-one (77-LH-28-1) as a Model for the Rational Design of a Novel Class of Brain Penetrant Ligands with High Affinity and Selectivity for Dopamine D4Receptor / F. Del Bello, A. Bonifazi, G. Giorgioni, C. Cifani, M.V. Micioni Di Bonaventura, R. Petrelli, A. Piergentili, S. Fontana, V. Mammoli, H. Yano, R. Matucci, G. Vistoli, W. Quaglia. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 61:8(2018 Apr), pp. 3712-3725. [10.1021/acs.jmedchem.8b00265]

1-[3-(4-Butylpiperidin-1-yl)propyl]-1,2,3,4-tetrahydroquinolin-2-one (77-LH-28-1) as a Model for the Rational Design of a Novel Class of Brain Penetrant Ligands with High Affinity and Selectivity for Dopamine D4Receptor

G. Vistoli;
2018-04

Abstract

In the present article, the M1mAChR bitopic agonist 1-[3-(4-butylpiperidin-1-yl)propyl]-1,2,3,4-tetrahydroquinolin-2-one (77-LH-28-1, 1) has been demonstrated to show unexpected D4R selectivity over D2R and D3R and to behave as a D4R antagonist. To better understand the structural features required for the selective interaction with the D4R and to obtain compounds unable to activate mAChRs, the aliphatic butyl chain and the piperidine nucleus of 1 were modified, affording compounds 2-14. The 4-benzylpiperidine 9 and the 4-phenylpiperazine 12 showed high D4R affinity and selectivity not only over the other D2-like subtypes, but also over M1-M5mAChRs. Derivative 12 was also highly selective over some selected off-targets. This compound showed biased behavior, potently and partially activating Giprotein and inhibiting β-arrestin2 recruitment in functional studies. Pharmacokinetic studies demonstrated that it was characterized by a relevant brain penetration. Therefore, 12 might be a useful tool to better clarify the role played by D4R in disorders in which this subtype is involved.
Molecular Medicine; Drug Discovery; Pharmaceutical Science
Settore CHIM/08 - Chimica Farmaceutica
Article (author)
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/598912
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