{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T18:05:01Z","timestamp":1791914701662,"version":"4.3.4"},"reference-count":45,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,2,26]],"date-time":"2025-02-26T00:00:00Z","timestamp":1740528000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"FIRB of MURST (Italian Ministry of Education, Universities, and Research","award":["RBNE03YA3L-2005"],"award-info":[{"award-number":["RBNE03YA3L-2005"]}]},{"name":"FIRB of MURST (Italian Ministry of Education, Universities, and Research","award":["FPI000065"],"award-info":[{"award-number":["FPI000065"]}]},{"name":"Fondo di Ricerca di Ateneo, University of Camerino","award":["RBNE03YA3L-2005"],"award-info":[{"award-number":["RBNE03YA3L-2005"]}]},{"name":"Fondo di Ricerca di Ateneo, University of Camerino","award":["FPI000065"],"award-info":[{"award-number":["FPI000065"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Parkinson\u2019s disease (PD) represents a growing challenge to global health, as it involves millions of people. The high grade of disability is due to the loss of dopaminergic neuron activity, and levodopa is the gold-standard therapy used to restore dopamine in the dopamine-denervated regions. Another therapeutic approach is the use of A2A adenosine receptor antagonists and, among them, istradefylline is the only one currently approved for therapy in association with levodopa. In this work, we synthesized A2A adenosine receptor antagonists represented by 9-ethyl-2,8-disubstituted adenine derivatives, which were tested at human adenosine receptors in binding and functional assays. These compounds showed A2A adenosine receptor-binding affinities in the low nanomolar range and 1, 4, and 5 exhibited good potency in the functional assays. Hence, they were evaluated in in vivo rat models of PD, where they were demonstrated to revert haloperidol-induced catalepsy and potentiate levodopa-induced contralateral rotations in 6-hydroxydopamine-lesioned rats. The most potent derivative, 4, was then evaluated in the tacrine model, where it reduced the tremulous jaw movements, therefore demonstrating an action on parkinsonian tremor. These data revealed 8-ethoxy-2-phenethoxy-9-ethyladenine (4) as an A2A adenosine receptor antagonist endowed with antiparkinsonian effects and as a good candidate to treat the disease.<\/jats:p>","DOI":"10.3390\/cells14050338","type":"journal-article","created":{"date-parts":[[2025,2,26]],"date-time":"2025-02-26T06:15:33Z","timestamp":1740550533000},"page":"338","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["A2A Adenosine Receptor Antagonists and Their Efficacy in Rat Models of Parkinson\u2019s Disease"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5172-651X","authenticated-orcid":false,"given":"Andrea","family":"Spinaci","sequence":"first","affiliation":[{"name":"Medicinal Chemistry Unit, School of Pharmacy, University of Camerino, Via Madonna delle Carceri, I-62032 Camerino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8383-0813","authenticated-orcid":false,"given":"Michela","family":"Buccioni","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry Unit, School of Pharmacy, University of Camerino, Via Madonna delle Carceri, I-62032 Camerino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6616-6885","authenticated-orcid":false,"given":"Diego","family":"Dal Ben","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry Unit, School of Pharmacy, University of Camerino, Via Madonna delle Carceri, I-62032 Camerino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2082-6638","authenticated-orcid":false,"given":"Beatrice","family":"Francucci","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry Unit, School of Pharmacy, University of Camerino, Via Madonna delle Carceri, I-62032 Camerino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl-Norbert","family":"Klotz","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Pharmakologie und Toxikologie, Universit\u00e4t W\u00fcrzburg, Versbacher Str. 9, D-97078 W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriella","family":"Marucci","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry Unit, School of Pharmacy, University of Camerino, Via Madonna delle Carceri, I-62032 Camerino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7296-3197","authenticated-orcid":false,"given":"Nicola","family":"Simola","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Section of Neuroscience, University of Cagliari, Cittadella Universitaria, SP 8, Km 0.700, I-09042 Monserrato, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Micaela","family":"Morelli","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Section of Neuroscience, University of Cagliari, Cittadella Universitaria, SP 8, Km 0.700, I-09042 Monserrato, Italy"},{"name":"Neuroscience Institute, National Research Council of Italy (CNR), Cagliari Cittadella Universitaria, SP 8, Km 0.700, I-09042 Monserrato, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4911-1735","authenticated-orcid":false,"given":"Annalisa","family":"Pinna","sequence":"additional","affiliation":[{"name":"Neuroscience Institute, National Research Council of Italy (CNR), Cagliari Cittadella Universitaria, SP 8, Km 0.700, I-09042 Monserrato, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5304-5232","authenticated-orcid":false,"given":"Rosaria","family":"Volpini","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry Unit, School of Pharmacy, University of Camerino, Via Madonna delle Carceri, I-62032 Camerino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2004-1531","authenticated-orcid":false,"given":"Catia","family":"Lambertucci","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry Unit, School of Pharmacy, University of Camerino, Via Madonna delle Carceri, I-62032 Camerino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,26]]},"reference":[{"key":"ref_1","unstructured":"(2025, February 13). 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