{"id":"cce8e01d-40b2-5d25-8cd6-503850937b10","stable_key":"6660bba2-4fa0-590a-bf52-9803a24bea9f:taar1-null","predicate":"context_dependent_observation","statement":"Modafinil did not directly activate TAAR1 but changed phenethylamine responses with particular coexpressed transporters.","claim_class":"observational","status":"source_recorded","evidence_grade":"ungraded","direction":"context_dependent","is_public":true,"mechanism_event_id":"0eea7915-b14d-5d7b-8f75-077ab436610a","mechanism_event_label":"Modafinil did not directly activate TAAR1 but changed phenethylamine responses with particular coexpressed transporters.","subject":{"id":"624e6a4b-f96d-5d12-8206-30d1e1715c26","slug":"modafinil","display_name":"Modafinil","entity_type_key":"drug"},"object":{"id":"02fff1f5-8333-5e83-a800-65c12d1622fd","slug":"taar1-assay","display_name":"TAAR1 receptor activation assay","entity_type_key":"cellular_process"},"evidence_count":1,"mechanism_event":{"id":"0eea7915-b14d-5d7b-8f75-077ab436610a","stable_key":"6660bba2-4fa0-590a-bf52-9803a24bea9f:taar1-null-event","event_type":"experimental_observation","label":"Modafinil did not directly activate TAAR1 but changed phenethylamine responses with particular coexpressed transporters.","description":"A rhesus-monkey PET study detected both DAT and NET occupancy after intravenous modafinil. In human-transporter cell assays, dopamine uptake was inhibited more potently than norepinephrine uptake; serotonin uptake inhibition was much weaker. The same work found no direct TAAR1 activation, but altered phenethylamine responses when TAAR1 was coexpressed with particular transporters. This distinguishes **direct receptor agonism from transporter-dependent modulation**. Monkey intravenous target engagement does not establish the contribution of human NET at oral therapeutic exposure. [Madras et al., 2006](https://pubmed.ncbi.nlm.nih.gov/16885432/)","status":"provisional","compartment":null,"participants":[{"entity":{"id":"624e6a4b-f96d-5d12-8206-30d1e1715c26","slug":"modafinil","display_name":"Modafinil","entity_type_key":"drug"},"role":"tested factor","stoichiometry":null,"state_label":"Modafinil alone or with phenethylamine/transporter coexpression","sequence_order":0,"notes":""},{"entity":{"id":"02fff1f5-8333-5e83-a800-65c12d1622fd","slug":"taar1-assay","display_name":"TAAR1 receptor activation assay","entity_type_key":"cellular_process"},"role":"measured outcome","stoichiometry":null,"state_label":"mixed","sequence_order":1,"notes":""}]},"contexts":[{"dimension":"evidence_access","value_text":"Primary indexed abstract checked; full methods and figures not comprehensively reviewed.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_contrast","value_text":"{\"intervention\": \"Modafinil alone or with phenethylamine/transporter coexpression\", \"comparator\": \"Corresponding receptor-only/ligand controls\", \"endpoint\": \"Modafinil did not directly activate TAAR1 but changed phenethylamine responses with particular coexpressed transporters.\", \"effect_direction\": \"mixed\", \"combination\": \"single\", \"conditions\": []}","comparator":null,"unit":null,"notes":"Explicit extracted experimental comparison; source-derived draft.","entity":null},{"dimension":"experimental_model","value_text":"Receptor/transporter coexpression assays; direct agonism separated from transporter-dependent modulation.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"interpretation_status","value_text":"Source-derived extraction of a fact-checked reference; access is explicit, not independent raw-data verification.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"Interpret only within the recorded preparation, exposure and comparator. The complete source passage retains qualifications; unspecified doses/timing have not been extracted here. No clinical efficacy, nutrient deficiency or unique molecular mediation is inferred.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"plain_language","value_text":"Modafinil did not directly activate TAAR1 but changed phenethylamine responses with particular coexpressed transporters.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"Modafinil occupies dopamine and norepinephrine transporters in vivo and modulates the transporters and trace amine activity in vitro. | 2006 | DOI 10.1124/jpet.106.106583 | PMID 16885432 | https://pubmed.ncbi.nlm.nih.gov/16885432/","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"source_locator","value_text":"Reviewed reference lines 85-85; exact primary location described in quoted passage where extracted.","comparator":null,"unit":null,"notes":"","entity":null}],"evidence":[{"id":"ecbf3765-ce2f-5584-a18d-876ff9213f43","evidence_kind":"source_excerpt","locator":"Lines 85-85","start_line":85,"end_line":85,"excerpt":"A rhesus-monkey PET study detected both DAT and NET occupancy after intravenous modafinil. In human-transporter cell assays, dopamine uptake was inhibited more potently than norepinephrine uptake; serotonin uptake inhibition was much weaker. The same work found no direct TAAR1 activation, but altered phenethylamine responses when TAAR1 was coexpressed with particular transporters. This distinguishes **direct receptor agonism from transporter-dependent modulation**. Monkey intravenous target engagement does not establish the contribution of human NET at oral therapeutic exposure. [Madras et al., 2006](https://pubmed.ncbi.nlm.nih.gov/16885432/)","model_system":"Receptor/transporter coexpression assays; direct agonism separated from transporter-dependent modulation.","directness":"reported_statement","verification_status":"source_recorded","notes":"Exact excerpt of the retained AI-assisted reviewed reference; primary sources are cited in primary_references and access scope is retained. 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