title: Dissection of N,N-diethyl-N'-phenylpiperazines as α7 nicotinic receptor silent agonists.
abstract: The α7 nicotinic acetylcholine receptor (nAChR) is a target for control of inflammation-related phenomena via compounds that are able to selectively induce desensitized states of the receptor. Compounds that selectively desensitize, without facilitating significant channel activation, are termed 'silent agonists' because they can be discriminated from antagonists by the currents evoked with co-application with type II positive allosteric modulators (PAMs). One example is N,N-diethyl-N'-phenyl-piperazine (diEPP) (J. Pharm. Exp. Ther.2014, 350, 665). We used Ullmann-type aryl amination to synthesize a panel of 27 compounds related to diEPP by substitutions at the aryl ring and in the linkage between the piperazine and phenyl rings. Two-electrode voltage clamping of the human α7 nAChR expressed in Xenopus oocytes revealed that it was possible to tune the behavior of compounds to show enhanced desensitization without corresponding partial agonist activity such that trifluoromethyl and carboxamide aryl substituents showed 33 to 46-fold larger PAM-dependent net-charge responses, indicating selective partitioning of the ligand receptor complexes into the desensitized state.
authors.affiliation: Department of Chemistry, Biochemistry Division, University of Florida, Gainesville, FL 32611, USA.
authors.forename: Marta
authors.initials: M
authors.lastname: Quadri
authors.affiliation: Department of Pharmacology and Therapeutics, University of Florida, College of Medicine, Gainesville, FL 32610, USA.
authors.forename: Roger L
authors.initials: RL
authors.lastname: Papke
authors.affiliation: Department of Chemistry, Biochemistry Division, University of Florida, Gainesville, FL 32611, USA. Electronic address: horen@chem.ufl.edu.
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Horenstein
mesh_terms: D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000819:agonists* / Q000378:metabolism
chemical_list: D010879:Piperazines; D064569:alpha7 Nicotinic Acetylcholine Receptor
keywords: Desensitization; Electrophysiology; Nicotinic acetylcholine receptor; Silent agonist