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Highly selective D4R compounds may provide a valuable tool to elucidate D4R function and assess their potential as non-stimulant ADHD treatments.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>This study examined the behavioral effects of two novel D4R drugs, namely, FMJ-01-38 (high-efficacy partial agonist) and FMJ-01-54 (full antagonist) in adolescent spontaneously hypertensive rats (SHR\/NCrl), a validated ADHD animal model, and Wistar (control) rats.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Rats received intraperitoneal injections of FMJ-01-38 or FMJ-01-54 (5\u201310\u00a0mg\/kg), or vehicle prior to behavioral assays assessing locomotor activity (open field tests), recognition memory (novel object preference test), spatial working memory (Y-maze test), and impulsivity (delay discounting task).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>FMJ-01-38 dose-dependently reduced locomotor hyperactivity and improved spontaneous alternation in SHR\/NCrl; at 5\u00a0mg\/kg, it also enhanced novel object preference and reduced impulsive choice and action, indicating attenuation of ADHD-like behaviors and improved cognitive function. FMJ-01-54 produced similar improvements in Y-maze and novel-object performance without altering locomotor activity or impulsivity of SHR\/NCrl, suggesting selective cognitive improvement. In Wistar rats, FMJ-01-38 increased novel object preference only at the 5\u00a0mg\/kg dose, while FMJ-01-54 treatment did not produce any significant behavioral effects.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings demonstrate that D4R modulation, through either partial agonism or antagonism, differentially ameliorates ADHD-related behaviors and improves cognitive performance. Both FMJ-01-38 and FMJ-01-54 produced minimal effects in control animals, suggesting pathology-specific efficacy and highlighting D4R ligands as promising non-stimulant therapeutic candidates for ADHD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00213-026-07112-w","type":"journal-article","created":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T02:36:50Z","timestamp":1781750210000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Novel dopamine 4 receptor ligands differentially ameliorate ADHD-like behaviors in spontaneously hypertensive rats"],"prefix":"10.1007","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2046-522X","authenticated-orcid":false,"given":"Ike C.","family":"de la Pe\u00f1a","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha","family":"Andino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley","family":"Amis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad A.","family":"Alkhatib","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1845-9373","authenticated-orcid":false,"given":"Thomas M.","family":"Keck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1907-431X","authenticated-orcid":false,"given":"Comfort A.","family":"Boateng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,18]]},"reference":[{"issue":"2","key":"7112_CR1","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1021\/acsptsci.5c00646","volume":"9","author":"M Alkhatib","year":"2026","unstructured":"Alkhatib M, Jakobs FM, Hanson JN, Nilson AN, Moritz AE, Li T, Faibille AB, Bourn LA, Ramdhan PA, Ricchezza J 4th, Jordan S, Panasis D, Nguyen N, Kasarla N, Wang B, Garcia SS, Saez J, Paule J, Lee CB, Rais R, Slusher BS, Sibley DR, Li C, Keck TM, Boateng CA (2026) Bioisosteric replacement of amides with 1,2,3-triazoles improves dopamine D4 receptor ligand pharmacokinetics. 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