European Journal of Pharmacology, 182 (1990) 91-100

91

Elsevier EJP 51342

Electrophysiological characterization of a novel potent and orally active N M D A receptor antagonist: CGP 37849 and its ethylester CGP 39551 Mario F. Pozza, Hans-Rudolf Olpe, Felix Brugger and Graham E. Fagg Research and Development Department, Pharmaceuticals Division, Ciba-Geigy, Ltd., CH-4002 Basel, Switzerland

Received 26 January 1990, accepted 20 March 1990

The selectivity and potency of the novel competitive N-methyl-D-aspartate (NMDA) receptor antagonists, CGP 37849 and CGP 39551, were investigated in vitro and in vivo using electrophysiological approaches. Like the reference blocker DL-AP5, both compounds acted in vitro (hippocampus, substantia nigra, spinal cord) to antagonize the excitatory actions of exogenously administered NMDA as well as the synaptically elicited, physiological NMDA receptor responses in hippocampus and spinal cord. In all isolated preparations CGP 37849 was more potent than CGP 39551, and 5- to 10-fold more potent than DL-AP5. Neither compound showed any marked effect on responses evoked by quisqualate and kainate. NMDA excited dopaminergic cells in the pars compacta region of the substantia nigra in a concentration-dependent manner. This effect also could be selectively antagonized by CGP 37849 and CGP 39551. In the anaesthetized rat, excitatory responses of hippocampal pyramidal cells evoked by iontophoretic application of NMDA were antagonized by CGP 37849 and CGP 39551 following their oral administration without reducing quisqualate or kainate responses. In contrast to the in vitro situation, CGP 39551 was more potent than CGP 37849 in vivo. Effective doses were 30 mg/kg p.o. for CGP 39551 and 100 mg/kg p.o. for CGP 37849. In conclusion, it is demonstrated that CGP 37849 and CGP 39551 selectively antagonize NMDA evoked neuronal responses in vivo and in vitro and that the drugs are centrally active following their oral administration. Electrophysiology; CGP 37849; CGP 39551; AP5; Hippocampus; Substantia nigra; Spinal cord; NMDA receptor competitive antagonists; (Rat)

1. Introduction L-Glutamate and structurally related acidic amino acids are found throughout the mammalian central nervous system (Cotman et al., 1987). The excitatory actions of such amino acids are mediated by three receptor subtypes which are named according to the selective agonists: N-methyl-Daspartate (NMDA), kainate and quisqualate (aamino-3-hydroxy-5-methyl-4-isoxazolepropionate, A M P A ) (McLennan and Lodge, 1979; Watkins

Correspondence to: M.F. Pozza, Research and Development Department, Pharmaceuticals Division, Ciba-Geigy, Ltd., CH4002 Basel, Switzerland.

and Evans, 1981; Foster and Fagg, 1984; Watkins and Olverman, 1987). The most extensively studied of these receptors is the NMDA-preferring subtype. The introduction of the selective and potent competitive N M D A receptor antagonists D-2amino-5-phosphonopentanoic acid (AP5), D-2amino-7-phosphonoheptanonic acid (AP7), 3-(2carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) and cis-4-phosphonomethyl-2-piperidine carboxylic acid (CGS 19755) (Watkins and Olverman, 1987; Olverman et al., 1986; Lehmann et al., 1987; 1988) has been instrumental in characterizing the properties of N M D A receptors, their roles in brain function and their potential therapeutic applications (Meldrum, 1985; Fagg et al., 1986;

0014-2999/90/$03.50 © 1990 Elsevier Science Publishers B.V. (Biomedical Division)

92 Mayer and Westbrook, 1987; Monaghan et al., 1989). A limitation of these compounds, however is that they do not readily cross lipid permeability barriers and are not active when administered orally. Recently we described a novel analogue of the phosphono amino acid, A P 5 : C G P 37849 (DL(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid), which shows high affinity for [3H]CPP binding sites (K i 35 nM) and is a potent anticonvulsant (EDs0 21 m g / k g ) following oral administration to rats and mice (Fagg et al., 1988; in press; Schmutz et al., 1988). The aim of the present investigation was to comprehensively examine the properties of C G P 37849 and its carboxyethylester, C G P 39551, by means of electrophysiological approaches. To this end, we studied the potency and selectivity of C G P 37849 and C G P 39551 as antagonists of exogenously applied agonists and synaptically evoked responses in the hippocampus, substantia nigra and the spinal cord in vitro, and in the hippocampus in vivo following i.v. or oral administration. These data provide a critical link between biochemical and behavioural studies; we show that C G P 37849 and C G P 39551 are potent and selective N M D A receptor antagonists, with marked central activity following administration by the oral route.

2. Materials and methods

2.1. Hippocampus in vitro

Experiments were performed on transverse hippocampal slices (400 ttm) prepared from male Tif : RAI f(SPF) rats (150-200 g weight) essentially as described by Olpe and Lynch (1982) and by Haas and Ryall (1980). The slices were allowed to stabilize in a humidified slice chamber and were perfused with an artificial cerebrospinal fluid (ACSF). This comprised (in mM): NaC1 124; KCI 2.5; K H 2 P O 4 1.25; CaCI 2 2.5; MgSO 4 2.0; N a H C O 3 26 and glucose 10 (307 _+ 2 m O s m / k g ) . The ACSF was gassed with a 95% 02-5% CO 2 mixture at 32°C. Extracellular recordings from the stratum pyramidale region of area CA1 were

made using glass micropipettes filled with 4 M NaC1 having resistances of 5-10 M$2. (a) Agonist-antagonist interactions were investigated by applying sub-maximal concentrations (10 ~M) of N M D A , quisqualate and kainate at intervals of 5-10 min in the presence or absence of test blockers, and by plotting the firing rate of single neurons (number of action potentials in 5 or 10 s periods) on a pen-recorder. All substances were applied via the perfusion fine to submerged slices. (b) The effects of antagonists on long-term potentiation (LTP) were investigated using slices maintained in an interface-chamber as described by Collingride et al. (1983a,b). Population spikes were evoked by stimulating the Schaffer collateral-commissural pathway using a bipolar 50 /~M Pt/iridium electrode (frequency 0.05 Hz) and LTP was induced by brief tetanic stimulation (100 H z / 0 . 3 s). Antagonists were applied by pressure ejection from a micropipette onto the stratum radiatum of area CA1. (c) The ability of test drugs to block synaptically-evoked epileptiform activity was investigated as described by Coan and Collingridge (1985). The concentration of Mg 2+ in the ACSF was lowered from 2 m M to nominally 0.1 mM, thereby reducing the physiological blockade of N M D A receptors (Nowak et al., 1984) and multiple population spikes were evoked by submaximal stimulation of the Schaffer collateral-commissural fibers (frequency 0.125 Hz). Drugs were applied for periods of 10 min and their effects on the first and second population spikes were determined. 2.2. Substantia nigra in vitro

Recordings were made from coronal midbrain slices (400 /~m) obtained from male T i f : R A I f(SPF) rats weighing 110-130 g. Slices were maintained in a humidified interface chamber and were perfused with gassed ACSF at a temperature of 32°C. Extracellular recordings were made from dopaminergic neurons in the pars compacta region of the substantia nigra. Cells were identified on the basis of their characteristic action potentials (Grace and Bunney, 1983) and decreased firing

93 rates in response to dopamine (Pinnock, 1983). Agonists were bath-applied in a cumulative manner and the firing rate of single neurons was recorded (number of action potentials within 30 s periods) and not only plotted on a chart-recorder but also digitized and stored on a computer harddisk. A similar approach has been used by other investigators to determine potencies of excitatory amino acid antagonists (Birch et al., 1988). 2.3. Spinal cord in vitro Experiments were carried out using hemisected spinal cords isolated from 7-15 day old rats [Tif : RAI f(SPF)] essentially as described by Evans (Evans, 1978). Under urethane anaesthesia, the spinal cord with attached dorsal and ventral roots (L3-L6) was excised, sagittally hemisected and transferred onto a perfusion block. The preparation was superfused (1 m i / m i n ) with gassed ACSF at 25°C. A dorsal root (L4) was submaximally stimulated using a pair of silver wire electrodes (1 stimulus/min) and the resultant dorsal rootventral root potential (DR-VRP) was recorded from the corresponding ventral root. Agonists were applied via the superfusion system for periods of 50 or 60 s every 10 rain. The actions of test antagonists on responses induced by excitatory amino acids were determined by comparing the amplitudes of the N M D A - i n d u c e d depolarizations before and during the application of the antagonist. Tetrodotoxin (TTX) was not used in these experiments because this allowed study of the effects of antagonists on both agonist induced and synaptically evoked responses; however, N M D A antagonists such as AP5 have been shown previously to selectively block N M D A - i n duced depolarizations in the presence of T T X (Evans et al., 1982). 2.4. Ionophoretic experiments in vivo Male rats [Tif: RAI f(SPF)] weighing 280-320 g were anaesthetized with chloral hydrate (400 m g / k g i.p., supplemented approximately each hour) and mounted in a stereotaxic frame with the nose bar located 5 m m above the ear bar. N M D A (0.01 M), quisqualate (0.01 M) and kainate (0.01

M) were administered ionophoretically by means of four-barrelled micropipettes close to hippocampal pyramidal neurons of the CA1 area. The fourth, recording electrode was filled with 4 M NaC1. Pyramidal neurons were not spontaneously active and were activated upon administration of excitatory amino acids. Currents applied to each barrel were adjusted to produce similar agonist responses and the firing rates of two to four neurons (action potentials in 3-10 s periods) were plotted on a chart recorder. Once stable responses were obtained for N M D A , quisqualate and kainate, test antagonists were administered intravenously or via an oesophageal cannula in a cumulative manner at intervals of 3 h. Antagonist action was determined by comparing the increases in agonist-induced firing in the absence of test blockers and 30 rain or 3 h following i.v. or oral drug administration, respectively. Standard laboratory chemicals were obtained from F L U K A . Sigma supplied N M D A and kainate, and Tocris Neuramin supplied quisqualate and DL-AP5.

3. Results 3.1. Studies of CGP 37849 and CGP 39551 in vitro 3.1.1. Potency and selectivity In all three isolated preparations employed here (hippocampal and nigral slices, hemisected spinal cord), C G P 37849 potently and selectively antagonized responses evoked by N M D A , without affecting those elicited by other excitatory amino acids. A typical experiment illustrating its potency in the spinal cord is shown in fig. 1. In this tissue, C G P 37849 blocked the long-latenc~¢ component of the D R - V R P and reduced depolarizations evoked by 30 /~M N M D A in a concentration-dependent manner; threshold and maximally effective antagonist concentrations were about 0.1 and 10/tM, respectively. In the same experiment, DLAP5 was a much less potent antagonist, a concentration of 1 / t M reducing the N M D A response to about the same level as 0 . 1 / t M C G P 37849 (17 and 21% antagonism, respectively); on this basis,

94

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NMDA ~ou~ J Fig. 1. Potency of C G P 37849. Antagonism of N M D A - i n d u c e d ventral root responses in the rat hemisected spinal cord in vitro by C G P 37849 and DL-AP5. N M D A (30/~M, A) evoked strong depolarizations of the ventral root which could progressively be reduced by increasing concentrations of C G P 37849 (0.1, 1 and 10 ~M) or by DL-AP5 (1 v M ) applied for the duration indicated by the horizontal bars. At these concentrations, the D R - V R P was also reduced in size. The intervals in the trace (A, B, C) represent 5, 35 and 20 rain, respectively. This experiment was repeated 4 times with similar results. Recordings from a ventral root (L4).

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Fig. 2. Selective blockade of N M D A - i n d u c e d ventral root responses in the hemisected rat spinal cord in vitro by (a) C G P 37849 and (b) C G P 39551. (a) Dorsal root-evoked ventral roots responses (DR-VRPs) and depolarizing ventral root potentials evoked by L-glutamate (Glu), N M D A , quisqualate (Quis) and kainate (Kai) before (upper trace), during superfusion with 1 ~ M C G P 37849 (middle trace) and after antagonist wash-out (lower trace). (b) Similar experiment as in (a), but using 1 v M and 10 ~tM C G P 39551 to antagonize D R - V R P s and agonist-induced depolarizing responses. Each antagonist was tested in three different experiments with similar results. Recordings from a ventral root (L4).

95

DL-AP5 appears to be approximately 10-fold less potent than CGP 37849. The selectivity of CGP 37849 in the spinal cord was analysed by examining the antagonism of ventral root depolarizations evoked by NMDA, quisqualate, kainate and L-glutamate. At a concentration of 1 #M, CGP 37849 reduced part of the slow components of the DR-VRP and clearly blocked the response induced by NMDA, slightly reduced the depolarization elicited by L-glutamate ( - 10% antagonism) and had no marked effect on responses evoked by quisqualate or kainate (fig. 2a). The selectivity of C G P 37849 for the N M D A receptor response was maintained even at a 10-fold higher concentration of the antagonist (10/zM), at which the NMDA-evoked depolarization is completely abolished (fig. 1); again, responses to quisqualate and kainate were unaffected (not shown). Similar findings were made in both the hippocampal and nigral slices, recording from CA1 pyramidal cells and identified dopaminergic neurons, respectively. CGP 37849 was observed to have no effect on the spontaneous neuronal firing rate, but in both tissues blocked the increases in firing induced by 10 # M N M D A without affecting responses to kainate or to quisqualate (note that, although all three agonists increased the CA1 neuronal firing rate, only N M D A and kainate evoked consistent excitatory responses in the substantia nigra). As observed in the spinal cord, threshold concentrations for antagonism of N M D A responses were in the region of 0.1-0.5 ~tM. A repre6

sentative example of such an experiment in the substantia nigra slice is shown in fig. 3a. Figure 3b shows cumulative concentration-response curves to N M D A which illustrate the antagonist effect of CGP 37849 in the substantia nigra. CGP 37849, tested at concentrations of 0.5-3 /tM, reduced the response to N M D A and shifted the concentration-response curve to the right, indicating a competitive blockade of the N M D A receptor. After wash-out of the antagonist, the N M D A response returned to pre-drug levels. DL-AP5 was also shown to block NMDA-evoked responses in this preparation (not shown), but less potently than CGP 37849. Like C G P 37849, C G P 39551 selectively blocked NMDA-evoked excitations in vitro, but was of lower potency. Figure 2b shows a typical experiment in which 1 and 10 /~M CGP 39551 antagonized NMDA-, but not quisqualate- or kainate-evoked responses in the hemisected spinal cord.

3.1.2. Effect on long-term potentiation (LTP) Brief tetanic stimulation of the Schaffer collateral-commissural pathway in the hippocampal slice induced a large and long-lasting potentiation of the field EPSP and population spike (fig. 4); a single train of stimuli (100 Hz for 0.3 s) increased the amplitude of the population spike by 100 + 48% (n = 10). The induction of this effect was totally blocked by 30 ffM DL-AP5 and 1 ffM CGP 37849 applied by pressure ejection from micropipettes onto the apical dendrites of CA1 pyra225

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Fig. 3. C G P 37849 reduces N M D A - i n d u c e d increases in neuronal firing in the rat substantia nigra in vitro. (a) Representative trace showing the blockade of N M D A (N, 10 #M)-, but not kainate (K, 1 #M)-induced increases in neuronal firing rate by C G P 37849 (3 #M). (b) Log concentration-response curves from a single experiment describing the increase in neuronal firing rate evoked by N M D A before (zx) and following (A) addition of 2 # M C G P 37849. A single N M D A - e v o k e d response after wash-out of C G P 37849 is also shown (O). These experiments were repeated 3 times with similar results.

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midal neurons. Lower concentrations of drugs were evaluated but the concentrations mentioned were the minimal effective to clearly block induction of LTP. At these concentrations, neither drug affected the population spike amplitude elicited by low frequency (0.03 Hz) stimulation (fig. 4), although higher concentrations (e.g. 50 # M DL-AP5 and 5 ~tM C G P 37849) did reduce this response. Once induced the potentiated response was not reduced by both DL-AP5 and C G P 37849.

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3.1.3. Blockade of epileptiform spike discharges Stimulation of Schaffer collateral-commissural fibres in hippocampal slices bathed in low Mg z+containing medium evoked multiple spikes in CA1 pyramidal neurons that resembled seizure discharges. DL-AP5 and CGP 37849 suppressed the late spikes of such bursts (fig. 6) in a concentration-dependent manner, although CGP 37849 was at least 5 times more potent than DL-AP5 (fig. 7). At sufficient concentration, both compounds completely abolished the 3rd and later population spikes of such multiple spikes (fig. 6), while reducing the 2nd spike by about 50% (fig. 7). The first spike was unaffected by either antagonist at the highest test concentration of 10/~M. CGP 39551 was also shown to reduce burst firing in this paradigm, but was weaker than CGP 37849 (approximately equivalent to DL-AP5, not shown). 3.2. Studies of CGP 37849 and CGP 39551 in vivo CGP 37849 and CGP 39551 were also evaluated as antagonists of excitatory amino acid-evoked responses in the hippocampus in vivo. Both compounds, following oral or intravenous treatment, selectively and dose dependently depressed the increases in hippocampal neuronal firing rate induced by ionophoretically applied N M D A without affecting responses to quisqualate and kainate. In the case of CGP 37849, threshold doses were in the region of 30 m g / k g p.o. and below 1 m g / k g i.v. (based on measurements of response amplitudes 3 h and 15 min post-treatment, respectively),

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X Fig. 4. The induction of long-term potentiation (LTP) in CA1 hippocampal pyramidal neurons in vitro is blocked by C G P 37849. (A-C) Population spikes recorded from CA1 pyramidal neurons in response to stimulation of Schaffer collateral/ commissural fibers (A) before and (B,C) after brief tetanic stimulation (100 Hz, 0.3 s). In (B), tetanic stimulation was applied in the presence of C G P 37849 (1 ~M). Records are averages of four responses. (D) Chart record showing amplitude of population spikes during this experiments. A, B and C indicate points at which individual oscilloscope records (above) were samples. This experiment was repeated 3 times with similar results.

TABLE 1 Antagonism of N M D A - i n d u c e d excitatory responses in the rat hippocampus in vivo by C G P 37849 and C G P 39551. Values are m e a n s ± S.E.M. of data from three to five separate experiments (except a mean of two experiments). NT, not tested. Dose (mg/kg)

1

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Percent reduction of the control response by C G P 37849

C G P 39551

P.o.

I.v.

P.o.

I.v.

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43 a 97±3 NT NT

NT 23±9 85±6 93±6

NT NT 30±25 NT

97 AP5 10 pM

washout

CGP 37849 10 ~M

washout

5 mV

5 ms

Fig. 5. C G P 37849 and DL-AP5 suppress epileptiform spike discharges in CA1 pyramidal cells in vitro. Hippocampal slices were perfused with medium containing 0.1 /xM Mg 2+, and multiple population spikes were evoked in CA1 neurons by stimulation of Schaffer collateral/commissural fibers. C G P 37849 and DL°AP5 (10 # M ) suppressed the late components of such discharges without affecting the first spike. This experiment was repeated 5 times with similar results. Arrows (A) mark the stimulus artefact.

while complete blockade of N M D A - e v o k e d responses was apparent at doses of 10 m g / k g p.o. and 10 m g / k g i.v. (table 1). However, the latency % reduction of 2nd population spike 100

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to onset of antagonist action was quite different by the two administration routes. After a dose of 100 m g / k g p.o., C G P 37849 showed a latency of 30-40 min before clear antagonism of N M D A evoked responses was observed, whereas this occurred in 15-20 min following i.v. injection. C G P 39551 also selectively reduced N M D A elicited excitatory responses in the hippocampus in vivo (fig. 8). Interestingly, however, it was more potent than C G P 37849 following oral administration and less potent after i.v. injection (table 1). Thus, whilst 30 m g / k g C G P 37849 p.o. showed only threshold-level antagonism of N M D A - e v o k e d responses, the same dose of C G P 39551 was close to maximally effective (table 1).

concentration in pM Fig. 6. Concentration-response plots describing the suppression of epileptiform spike discharges by C G P 37849 and DL-AP5. Multiple spike discharges were evoked in hippocampal CA1 pyramidal cells as described in fig. 5, and the amplitude of the 2nd population spike was determined in the presence of various concentrations of C G P 37849 and DL-AP5. Values are m e a n s + (S.E.M.) of data from five separate experiments.

4. Discussion

The present data demonstrate that C G P 37849 is a potent and selective blocker of N M D A receptors throughout the central nervous system (hip-

98

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5 min. Fig. 7. Orally administered CGP 37849 and CGP 39551 selectivelyblock NMDA-inducedexcitations in the rat hippocampus in vivo. Representative chart records showing the increase in CA1 neuronal firing rate evoked by io'nophoretically-applied N M D A (N), quisqualate (Q) and kainate (K) in the urethane-anaesthetized rat. CGP 37849 and CGP 39551 were dissolved in physiologicalsaline and administered by means of an oesophageal cannula. Each experiment was performed 3-5 times with similar results; quantitative data from all experiments are given in table 1.

pocampus, substantia nigra and spinal cord). In all three regions examined, it antagonized NMDA-evoked responses at threshold concentrations in accordance with its potency in N M D A receptor binding assays (Fagg et al., 1988), and did not depress responses elicited by quisqualate or kainate. The results from the binding experiments indicated that C G P 37849 is approximately seven times more potent than DL-AP5 as an N M D A antagonist. Although the present results do not allow calculation of a precise potency ratio, the hippocampal experiments suggest a factor of about 5 and the results obtained from the spinal cord suggest that the difference could be a factor of approximately 10. C G P 37849 thus appears to be a potent and valuable tool for future studies of the role of N M D A receptors in brain function. Further evidence of the selectivity of C G P 37849 was obtained from studies of synaptically evoked responses in the hippocampus and spinal cord in vitro. In the hippocampal slice, the drug attenuated the amplitude of the late stimulus-evoked

population spikes (low Mg 2+ level) and suppressed the induction of LTP (as observed for other N M D A receptor blockers; see Collingridge et al., 1983a; Harris et al., 1984; Coan and Collingridge, 1985; 1987; Herron and Forsythe, 1989). However, it had no effect on the fast AP5insensitive component of the EPSP or population spike in either experimental paradigm, which is conistent with the notion that the fast synaptic response is mediated primarily by n o n - N M D A receptors (Coan and Collingridge, 1985; Mayer and Westbrook, 1987). In the spinal cord, C G P 37849 similarly had an effect on the longer latency, probably polysynaptic component of the DR-VRP. C G P 37849 thus seems to be a selective antagonist of the late or polysynaptic responses typically mediated by N M D A receptor mechanisms as has been shown for other selective N M D A blockers (Evans et al., 1981; for review see Mayer and Westbrook, 1987). An exceptional feature of C G P 37849 and C G P 39551 is their oral bioavailability. Competitive

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N M D A antagonists generally are highly polar molecules and do not traverse lipid permeability barriers easily. Recently, a number of such antagonists have been shown to exert central effects following i.v. or i.p. injection (Meldrum et al., 1983; Jones et al., 1984; De Sarro et al., 1985; Lodge et al., 1988), but none have been reported to exhibit a significant level of activity following oral administration. In the present experiments, the threshold dose of CGP 37849 for antagonism of NMDA-evoked responses in the hippocampus in vivo was 30 m g / k g p.o., and below 10 m g / k g after i.v. injection. The ethylester of CGP 37849, C G P 39551, was more potent after oral administration (threshold dose about 10 m g / k g p.o.) and less potent after i.v. treatment. Although one would predict that the antagonist doses required to block NMDA-evoked spiking in vivo might not be comparable with the doses to suppress electroshock-induced seizures in rats (since the concentrations of N M D A following ionophoretic application are unknown), these are in fact remarkably close (Schmutz et al., 1988). The present observations thus provide good evidence that the anticonvulsant actions of CGP 37849 and CGP 39551 in vivo are likely to be mediated via antagonism of N M D A receptor mechanisms. Comparison of the data reported here with those recently described by Lodge et al. (1988) indicates that, after i.v. injection, CGP 37849 is of similar potency in vivo to CGS 19755 and CPP (but more potent than AP5 or AP7). Moreover the latency to onset is approximately equal for all three compounds. Thus, CGP 37849, CPP and CGS 19755 appear to penetrate the blood-brain barrier to a similar extent. Of these substances, C G P 37849 is the only one reported to have central effects following oral administration (Fagg et al., 1988; Schmutz et al., 1988). Interestingly, the ethylester, CGP 39551, was substantially weaker than CGP 37849 as an antagonist of NMDA-evoked neuronal responses following i.v. dosage, but more potent after oral administration. In addition, its latency to onset of clear antagonistic effects was longer than for C G P 37849. These observations are consistent with the hypothesis that CGP 39551 functions as a more readily absorbable form of CGP 37849 in vivo. The finding

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Electrophysiological characterization of a novel potent and orally active NMDA receptor antagonist: CGP 37849 and its ethylester CGP 39551.

The selectivity and potency of the novel competitive N-methyl-D-aspartate (NMDA) receptor antagonists, CGP 37849 and CGP 39551, were investigated in v...
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