Egyed, Attila and Kiss, Dóra Judit and Pável, Zsófia and Rajna, Keve and Gaitonde, Supriya A. and Dubiel, Mariam and Loza, María Isabel and Szűcs, Edina and Borbély, Éva and Hajna, Zsófia Réka and Satala, Grzegorz and Vass, Márton and Szabó, Pál Tamás and Jósvay, Katalin and Bojarski, Andrzej J. and Stark, Holger and Helyes, Zsuzsanna and Pintér, Erika and Bouvier, Michel and Keserű, György Miklós (2025) The impact of secondary site interactions on the binding specificity of bitopic dopamine D2/D3 receptor ligands. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY REPORTS, 15. No. 100302. ISSN 2772-4174
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Abstract
Dysfunction of dopamine receptors and interruption of normal dopaminergic signaling have been linked to severe neuropsychiatric diseases such as schizophrenia, Parkinson's disease and depression. Although these receptors are among the most drug-targeted families of GPCRs, designing compounds with subtype-specific pharmacological profile remains challenging due to the structural similarities among the subtypes of the family. Considering the structural moieties of cariprazine, a prototypic drug with D3 receptor (D3R) preference, we report a library of bitopic analogues to explore how the orthosteric and secondary binding motifs, coupled with different linkers, affect D2R/D3R selectivity and activity. Compounds with promising dopamine receptor selectivities and binding affinities were further characterized on a GPCR panel and in functional assays. Our efforts resulted in an advanced lead compound (20b) with improved D3R and 5-HT2AR, as well as decreased D2R and 5-HT1AR potencies (EC50) compared to cariprazine. The cleaner receptor profile of this compound retained activities for the most important antidepressant mechanisms that were confirmed by reducing the depression-like behavior in mice.
| Item Type: | Article |
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| Additional Information: | Funding Agency and Grant Number: Network of European Funding for Neuroscience Research; National Brain Research Program of Hungary [2017-1.2.1-NKP-2017-00002 NAP 2.0, NAP2022-I-2/2022 NAP3.0]; National Drug Research and Development Laboratory [RRF-2.3.1-21-2022-00015]; NRDI Office; Hungarian Research Network (HUN-REN) [TKP2021-EGA-16]; National Research, Development and Innovation Fund of Hungary [EGA-16]; Hungarian National Research, Devel-opment and Innovation Office [OTKA K138046, OTKA K134214, OTKA FK137951]; Research Grant of the Medical School [KA-2023-07]; Deutsche Forschungsgemeinschaft [GRK2158]; Canadian Institute for Health Research [CIHR PJT-183758] Funding text: The authors are grateful for Katalin Fabian for the help in the pharmacokinetics sample preparation. The authors thank the financial support for the Network of European Funding for Neuroscience Research through the grant PSYBIAS. The authors are grateful for the KIFUE-NIIF Institute for granting computational time on the Hungarian HPC Infra-structure. This work was supported by a grant from the National Brain Research Program of Hungary (2017-1.2.1-NKP-2017-00002 NAP 2.0 and NAP2022-I-2/2022 NAP3.0) and National Drug Research and Development Laboratory (PharmaLab) project (RRF-2.3.1-21-2022-00015) sponsored by NRDI Office, as well as the Hungarian Research Network (HUN-REN, Chronic Pain Research Group, Pe cs) . Project no. TKP2021-EGA-16 has been implemented with the support provided from the National Research, Development and Innovation Fund of Hungary, financed under the EGA-16 funding scheme. Z. Helyes, E.P. and E .B. were supported by the Hungarian National Research, Devel-opment and Innovation Office (OTKA K138046, OTKA K134214 and OTKA FK137951, respectively) . Z.Hajna was supported by the Research Grant of the Medical School, University of Pe cs (KA-2023-07) . Support by Deutsche Forschungsgemeinschaft on GRK2158 is acknowledged (M. D, H.S.) . The work was supported in part by a Canadian Institute for Health Research (CIHR PJT-183758) to MB. |
| Subjects: | R Medicine / orvostudomány > RM Therapeutics. Pharmacology / terápia, gyógyszertan |
| SWORD Depositor: | MTMT SWORD |
| Depositing User: | MTMT SWORD |
| Date Deposited: | 10 Feb 2026 09:45 |
| Last Modified: | 10 Feb 2026 09:45 |
| URI: | https://real.mtak.hu/id/eprint/233662 |
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