title: Identification and pharmacological characterization of 3,6-diazabicyclo[3.1.1]heptane-3-carboxamides as novel ligands for the α4β2 and α6/α3β2β3 nicotinic acetylcholine receptors (nAChRs).
abstract: We have synthesized a novel series of compounds, 3,6-diazabicyclo[3.1.1]heptane-3-carboxamides, targeting both the α4β2 and α6/α3β2β3 nAChRs. Members of the obtained chemical library are partial or full agonists at both the high sensitivity (α4)2(β2)3 and α6/α3β2β3 nAChRs. 3-(Cyclopropylcarbonyl)-3,6-diazabicyclo[3.1.1]heptane (TC-8831 or compound 7 herein) demonstrated a safe in vitro pharmacological profile and the potential for reducing or preventing L-dopa-induced dyskinesias (LID) in several in vivo animal models [1-4]. In vivo metabolism studies in rat and in vitro metabolism studies in liver microsomes from human, rat, dog and monkey showed TC-8831 to be relatively stable. In vivo pharmacokinetic analysis in the rat confirmed brain penetration, with an average brain:plasma ratio of approximately 0.3 across time points from 0.5 to 4 h. Docking into homology models predicted alternative binding modes for TC-8831 and highlighted the importance of the cationic center, hydrogen-bond acceptor, and hydrophobic aliphatic features in promoting binding affinity to both nAChRs. Pharmacophore elucidation confirmed the importance of these key interactions. QSAR modeling suggested that binding affinity is primarily driven by ligand shape, relative positive charge distribution onto the molecular surface, and molecular flexibility. Of the two subtypes, ligand binding to α6β2β3 appears to be more sensitive to bulkiness and flexibility.
authors.affiliation: Targacept, Inc., 100 North Main Street, Winston-Salem, NC 27101-4165, USA.
authors.forename: Jon-Paul
authors.initials: JP
authors.lastname: Strachan
authors.affiliation: Targacept, Inc., 100 North Main Street, Winston-Salem, NC 27101-4165, USA. Electronic address: dckombo777@mail.com.
authors.forename: David C
authors.initials: DC
authors.lastname: Kombo
authors.affiliation: Targacept, Inc., 100 North Main Street, Winston-Salem, NC 27101-4165, USA.
authors.forename: Anatoly
authors.initials: A
authors.lastname: Mazurov
authors.affiliation: Targacept, Inc., 100 North Main Street, Winston-Salem, NC 27101-4165, USA.
authors.forename: Ronald
authors.initials: R
authors.lastname: Heemstra
authors.affiliation: Targacept, Inc., 100 North Main Street, Winston-Salem, NC 27101-4165, USA.
authors.forename: Balwinder S
authors.initials: BS
authors.lastname: Bhatti
authors.affiliation: Targacept, Inc., 100 North Main Street, Winston-Salem, NC 27101-4165, USA.
authors.forename: Rao
authors.initials: R
authors.lastname: Akireddy
authors.affiliation: Targacept, Inc., 100 North Main Street, Winston-Salem, NC 27101-4165, USA.
authors.forename: Srinivasa
authors.initials: S
authors.lastname: Murthy
authors.affiliation: Targacept, Inc., 100 North Main Street, Winston-Salem, NC 27101-4165, USA.
authors.forename: Lan
authors.initials: L
authors.lastname: Miao
authors.affiliation: Targacept, Inc., 100 North Main Street, Winston-Salem, NC 27101-4165, USA.
authors.forename: John E
authors.initials: JE
authors.lastname: Jett
authors.affiliation: Targacept, Inc., 100 North Main Street, Winston-Salem, NC 27101-4165, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Speake
authors.affiliation: Targacept, Inc., 100 North Main Street, Winston-Salem, NC 27101-4165, USA.
authors.forename: Merouane
authors.initials: M
authors.lastname: Bencherif
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D000882:Haplorhini; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism*
chemical_list: D000577:Amides; D008024:Ligands; D011978:Receptors, Nicotinic
keywords: Agonism; Binding; Modeling; nAChR; α4β2; α6/α3β2β3