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Noncompetitive Amine Uptake Inhibition by the New Antidepressant Pridefine
Author(s) -
DeMet Edward M.,
Vosmer Georgetta,
Halaris Angelos E.
Publication year - 1981
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.1981.tb01682.x
Subject(s) - antidepressant , chemistry , amine gas treating , biogenic amine , pharmacology , biochemistry , neuroscience , biology , serotonin , organic chemistry , hippocampus , receptor
Pridefine (AHR‐1118) is a pyrrolidine derivative with clinically established antidepressant efficacy. Previous work from this laboratory indicates that pridefine is a reuptake blocker of catecholamines and serotonin with weak releasing activity. This study characterized the mode of amine uptake inhibition by pridefine as noncompetitive. The uptake experiments were performed utilizing ouabain instead of zero‐degree controls to differentiate between the passive and active components of uptake. Furthermore, the passive component was resolved into diffusion and binding of substrate. Correction was made for the effects of ouabain on binding. Kinetic constants determined from Lineweaver‐Burk plots were: K m = 3 × 10 −7 M for NE, K m = 9 × 10 −8 M for DA, and K m = 3 × 10 −8 M for 5‐HT. Dixon analyses of uptake at various pridefine concentrations indicated noncompetitive inhibition with K i = 2.5 × 10 −6 M for NE uptake, K i = 2.0 × 10 −6 M for DA uptake, and K i = 1 × 10 −5 M for 5‐HT uptake. These constants compare well with IC 50 values for the same transmitters: NE, IC 50 = 2.4 × 10 −6 M; DA, IC 50 = 2.8 × 10 −6 M; 5‐HT, IC 50 = 1.0 × 10 −5 M. The in vitro results indicate that pridefine is relatively specific as a catecholamine uptake blocker. It differs from tricyclic antidepressants which are reportedly competitive inhibitors of monoamine uptake. The possible mechanisms by which pridefine acts as a noncompetitive inhibitor are discussed.