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A comparison between the in vivo and in vitro activity of five potent and competitive NMDA antagonists
Author(s) -
Lodge D.,
Davies S.N.,
Jones M.G.,
Millar J.,
Manallack D.T.,
Ornstein P.L.,
Verberne A.J.M.,
Young N.,
Beart P.M.
Publication year - 1988
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1988.tb11726.x
Subject(s) - nmda receptor , phosphonate , chemistry , kainate receptor , in vivo , glutamate receptor , pharmacology , antagonist , stereochemistry , memantine , biochemistry , ampa receptor , receptor , medicine , biology , microbiology and biotechnology
1 Phosphonate analogues of glutamate have been tested and compared as N‐methyl‐ d ‐aspartate (NMDA) antagonists in electrophysiological and binding experiments. The compounds tested were three established NMDA antagonists: d ‐2‐amino‐5‐phosphonopentanoate ( d ‐AP5), dl ‐2‐amino‐7‐phosphonoheptanoate ( dl ‐AP7), 3‐(2‐carboxypiperazin‐4‐yl)propyl‐l‐phospnonate (CPP), and two novel putative NMDA antagonists: 3‐(2‐carboxypiperidin‐4‐yl)propyl‐l‐phosphonate (CPPP) and 3‐(2‐carboxy‐piperidin‐4‐yl)methyl‐1‐phosphonate (CPMP). 2 When administered electrophoretically to rat spinal neurones in vivo , these compounds were found to be selective NMDA antagonists with little effect on excitations evoked by quisqualate and kainate. CPMP and CPPP were approximately equipotent with CPP and about 5 times more potent than d ‐AP5. 3 Following systemic administration, 2–5 mg kg −1 i.v. of CPP, CPMP and CPPP reduced NMDA‐evoked excitations by 70–100% whereas 50–100 mg kg −1 of d ‐AP5 and dl ‐AP7 produced a similar effect. The onset of the effects required 20–30 min and lasted more than six hours. 4 On bath application to cortical wedges, the IC 50 values (μ m ) for antagonism of 40 μ m NMDA were: CPP, 0.64 ± 0.06 (mean ± s.e.mean; n > 4); CPMP, 1.65 ± 0.13; CPPP 0.89 ± 0.09; d ‐AP5, 3.7 ± 0.32; dl ‐AP7, 11.1 ± 2.1; and dl ‐AP4 and dl ‐AP6 were inactive at 100 μ m . 5 In binding studies with [ 3 H]‐CPP, the K i values (n m ) were: CPP, 446 ± 150 (mean ± s.e.mean; n ≥ 3); CPMP, 183 ± 74 and CPPP, 179 ± 13 whereas against NMDA (10 μ m )‐stimulated [ 3 H]‐TCP (thienylcyclohexylpiperidine) binding the IC 50 values (μ m ) for CPMP and CPPP respectively were 5.6 ± 2.7 and 4.5 ± 2.2. 6 Systemic administration of CPPP and CPMP, at doses sufficient to antagonize NMDA, also reduced cardiovascular responses to 5‐hydroxytryptamine (Bezold‐Jarisch reflex). This illustrates a role for NMDA receptors in central cardiovascular control. 7 The results indicate the systemic doses of piperidine and piperazine analogues of d ‐AP5 which may be used for assessing the role of NMDA receptors in central synaptic function.