title: Design, synthesis, and pharmacological evaluation of azetedine and pyrrolidine derivatives as dual norepinephrine reuptake inhibitors and 5-HT(1A) partial agonists.
abstract: Compounds with combined norepinephrine reuptake inhibitor (NRI) and serotonin 1A (5-HT(1A)) partial agonist pharmacology may offer a new therapeutic approach for treating symptoms of neuropsychiatric disorders including ADHD, depression, and anxiety. Herein we describe the design and optimization of novel chemical matter that exhibits favorable dual NRI and 5-HT(1A) partial agonist activity. Lead compounds in this series were found to be devoid of activity at the dopamine transporter and were shown to be brain penetrant with high receptor occupancy.
authors.affiliation: Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, United States. martin.pettersson@pfizer.com
authors.forename: Martin
authors.initials: M
authors.lastname: Pettersson
authors.forename: Brian M
authors.initials: BM
authors.lastname: Campbell
authors.forename: Amy B
authors.initials: AB
authors.lastname: Dounay
authors.forename: David L
authors.initials: DL
authors.lastname: Gray
authors.forename: Longfei
authors.initials: L
authors.lastname: Xie
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: O'Donnell
authors.forename: Nancy C
authors.initials: NC
authors.lastname: Stratman
authors.forename: Kim
authors.initials: K
authors.lastname: Zoski
authors.forename: Elena
authors.initials: E
authors.lastname: Drummond
authors.forename: Gary
authors.initials: G
authors.lastname: Bora
authors.forename: Al
authors.initials: A
authors.lastname: Probert
authors.forename: Tammy
authors.initials: T
authors.lastname: Whisman
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001007:Anxiety / Q000188:drug therapy; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy; D001384:Azetidines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D003866:Depressive Disorder / Q000188:drug therapy; D004285:Dogs; D006801:Humans; D009638:Norepinephrine / Q000378:metabolism*; D011759:Pyrrolidines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D058825:Serotonin 5-HT1 Receptor Agonists / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D018759:Adrenergic Uptake Inhibitors; D001384:Azetidines; D011759:Pyrrolidines; D058825:Serotonin 5-HT1 Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; C032519:pyrrolidine; D009638:Norepinephrine