TiPS - February 1990 [Vol. 11] (1985) J. Pharmacol. Exp. Ther. 234, 49-56 5 Chalazonitis, A. and Crain, S. M. (1986) Neuroscience 17, 1181-1198 6 Miyake, M., Christie, M. J. and North, R. A. (1989) Proc. Natl Acad. Sci. USA 86, 3419-3422 7 Tortella, F. C. (1988) Trends Pharmacol. Sci. 9, 366-372 8 Zieglgansberger, W., French, E. D., Siggins, G. R. and Bloom, F. E. (1979) Science 205, 415-417 9 Shen, K-F. and Crain, S. M. (1989) Brain Res. 491, 227-242 10 Chen, G-G., Chalazonitis, A., Shen, K-F. and Crain, S. M. (1988) Brain Res. 462, 372-377 11 Crain, S. M. (1988) in Regulatory Role of Opioid Peptides (Illes, P. and Farsang, C., eds), pp. 186-201, VCH 12 Crain, S. M., Shen, K-F. and Chalazonitis, A. (1988) Brain Res. 455, 99-109 13 Higashi, H., Shinnick-Gallagher, P. and Gallagher, J. P. (1982) Brain Res. 251, 186-191 14 Shen, K-F. and Crain, S. M. Neuropharmacology (in press) 15 Pasternak, G. W. and Wood, P. J. (1986) Life Sci. 38, 1889-1898 16 Zukin, R. S., Eghbali, M., Olive, D.,


17 18 19 20 21 22 23 24 25 26 27 28 29 30

Unterwald, E. M. and Tempel, A. (1988) Proc. Natl Acad. Sci. USA 85, 4061--4065 Shen, K-F. and Crain, S. M. Brain Res. (in press) Gill, D. M. and Meren, R. (1978) Proc. Natl Acad. Sci. USA 75, 3050-3054 Stadel, J. M. and Lefkowitz, R. J. (1981) J. Cyclic Nucleotide Res. 7, 363-374 Ui, M. (1984) Trends Pharmacol. Sci. 5, 277-279 Jones, D. T. and Reed, R. R. (1989) Science 244, 790-795 Madison, D. V. and Nicoll, R. A. (1986) ]. Physiol. (London) 372, 245-259 Gray, R. and Johnston, D. (1987) Nature 327, 620-622 Rosenthal, W., Hescheler, J., Trautwein, W. and Schultz, G. (1988) FASEB J. 2, 2784-2790 Womble, M. D. and Wickelgren, W. O. Brain Res. (in press) Kayser, V., Besson, J. M. and Guilbaud, G. (1987) Brain Res. 414, 155-157 Knox, R. J. and Dickenson, A. H. (1987) Brain Res. 415, 21-29 Van der Kooy, D. (1986) Ann. NY Acad. Sci. 467, 154-168 Ballantyne, J, C., Loach, A. B. and Carr, D. B. (1988) Pain 33, 149-160 Sweeney, M. I., White, T. D. and

Noncompetitive excitatory amino acid receptor f EAA] antago n ists [ ph ,m cdogyJ David Lodge and Kenneth M. Johnson In the first article in this series, Watkins, Krogsgaard-Larsen and Honor4 outlined the structure-activity requirements at the receptor sites for excitatory amino acids in the mammalian CNS. The postsynaptic depolarizing actions of glutamate are thought to be mediated by NMDA, AMPA and kainate receptors. Here David Lodge and Kenneth M. Johnson review some of the recent developments in the pharmacology of other means by which the function of these receptors may be modulated. Divalent cations, phencyelidine-like drugs, glycine analogues and polyamines all modulate NMDA receptors whereas barbiturates and some arthropod toxins reduce channel responses to non-NMDA receptor agonists. Modes of action and implications for physiology and pathophysiology are discussed. There are at least three distinct classes of noncompetitive NMDA antagonist 1"2. The earliest of these to be established were the divalent cations including Mg 2+, Ni 2+ and Mn2+; of these Mg 2+ is the best known. Because the voltage-dependent block of the ion channel coupled to the NMDA

D. Lodge is Professor and Head of the Department of Veterinary Basic Sciences, The Royal Veterinary College, University of London, Royal College Street, London NW10TU, UK, and K. M. Johnson is Professor at the Department of Pharmacology, University of Texas Medical Branch, Galveston, TX 77550, USA.

receptor occurs well below the millimolar concentration of Mg 2+ found extracellularly in the CNS, Mg 2+ confers on the NMDA receptor-channel complex its physiologically important functional dependence on membrane potential, which will be discussed in detail in later articles in this series. Drugs that bind the other two established sites by which NMDA receptor function can be modulated are exemplified by phencyclidine and glycine. The phencyclidine site Phencyclidine (PCP) was the

31 32 33 34 35 36 37 38 39

Sawynok, J. (1989) J. Pharmacol. Exp. Ther. 248, 447-454 Sawynok, J., Sweeney, M. I. and White, T. D. (1989) Trends PharmacoL Sci. 10, 186-189 Chang, H. M., Kream, R. M. and Holz, G. G. (1988) Soc. Neurosci. Abstr. 14, 712 Belcher, G. and Ryall, R. W. (1978) Brain Res. 145, 303-314 Melzack, R. and Wall P. D. (1965) Science 150, 971-975 Pohl, M. et al. (1989) Neurosci. Lett. 96, 102-107 Xu, H., Smolens, I. and Gintzler, A. R. Brain Res. 504, 36--42 Makman, M. H., Dvorkin, B. and Crain, S. M. (1988) Brain Res. 445, 303-313 Sharma, S. K., Klee, W. A. and Nirenberg, M. (1975) Proe. Natl Acad. Sci. USA 72, 3092-3096 Collier, H. O. J. (1980) Nature 283, 62~629

DADLE: [DAIa2, DLeuS]enkephalin D A M G O : Tyr-DAla-Gly- [NMePhe]-NH(CH2)2-OH DPDPE: [DPen 2, DPenS]enkephalin TEA: tetraethyl a m m o n i u m ion U50488: 3,4-dichloro-N- [2- (1-pyrrolidinyl) c y c l o h e x y l ] b e n z e n e acetamide

first of the arylcyclohexylamines to be used in clinical practice as a dissociative anaesthetic. The term 'dissociative' refers to the lack of correlation between limbic and cortical EEG patterns rather than the bizarre behaviours seen after PCP administration. PCP was withdrawn from human use because of the high incidence of psychotomimetic emergence reactions and has been replaced by the shorter acting drug, ketamine. PCP has subsequently become a major drug of abuse particularly in the USA. How PCP produces its behavioural profile is of major interest to neuroscientists, especially those studying the aetiology of psychotic diseases. Interactions with several neurotransmitter systems and voltage-dependent ion channels are well established (Table I). There were some early clues indicating that dissociative anaesthetics might interact with glutamate receptors. For example, they had been shown to reduce both induction of long-term potentiation in the hippocampus and polysynaptic reflexes in the spinal cord (see Ref. 3 for review). Both these synaptic phenomena are dependent on NMDA receptor activation. Following the first conclusive demonstration by Lodge and colleagues in 1982 that PCP and ketamine were selective NMDA receptor antagonists, some

1990, ElsevierScience PublishersLtd. (UK) 0165-6147/90/$02.00


TiPS - February 1990 [Vol. 11]

TABLE I. Effect of PCP, MK801 and similar drugs on non-EAA receptors, transmitters and ion channels Transmitter/ ion channel




M K 8 0 1(IC5o2 ~,M) slightly less potent than PCP as inhibitor of [3H]noradrenaline uptake; ~-adrenoceptor antagonists reduce anticonvulsant actions of MK801

Snell, L. D., Yi, S-J. and Johnson, K. M. (1988) Eur. J. Pharmacol. 145, 223-226; Clineschmidt, B. V., Martin, G. E. and Bunting, P. R. (1982) DrugDev. Res. 2, 123-134


PCP (IC5o 0.5 pM) 280-fold more potent than MK801 as [3H]dopamine uptake inhibitor; effects of PCP on uptake, release and metabolism more like methylphenidate and amfonelic acid than amphetamine; effects of PCP, ketamine, dioxadrol, N-allyl-normetazocine and cyclazocine on uptake, release and haloperidol-induced metabolism do not correlate with [3H]PCP binding affinity

Snell, L. D., Yi, S-J. and Johnson, K. M. (1988) Eur. J. Pharmacol. 145, 223-226; Johnson, K. M. (1983) Fed. Proc. 42, 2579-2583; Johnson, K. M. and Snell, L. D. (1985) PharmacoL Biochem. Behav. 22, 731-735; Snell, L. D., Mueller, Z. L., Gannon, R. L., Silverman, P. B. and Johnson, K. M. (1984)J. Pharmacol. Exp. Ther. 231,261-269


PCP (K~ 96 ~M) 80-fold less potent than N-allyl-normetazooine as acetylcholinesterase inhibitor

Johnson, K. M. and Hillman, G. R. (1982) J. Pharm. PharmacoL 34, 462-464

Muscarinic cholinoceptor

antimuscarinic potency ([3H]QNB binding, IC5o 10 pM) similar to N-allyl-normetazocine and behaviourally inactive PCP metabolite; PCP lethality in mice markedly potentiated by oxotremorine, blocked by peripheral muscarinic cholinoceptor antagonist

Johnson, K. M. and Hillman, G. R. (1982) J. Pharm. Pharmacol. 34, 462-464; Johnson, K. M. (1982) Pharmacol. Biochem. Behav. 17, 53-57

Nicotinic cholinoceptor

PCP blocks preferentially the activated state of the nicotinic receptor in electric org~ln of Torpedo (Ki 2 IXM); block is voltage and time dependent; competes with similar potency for [3H]perhydrohistrionicotoxin binding site within channel

Albuquerque, E. X., Jsai, M-C., Aronstam, R. S., Eldefrawi, A. T. and EIderfrawi,M. F. (1980) MoL Pharmacol. 18, 167-178

K + channel

PCP prolongs action potential and inhibits delayed rectification in frog skeletal muscle; PCP inhibits component of 86Rb efflux in synaptosomes that corresponds to voltagegated, non-inactivating K+channel; dioxadrol and o benzomorphan pharmacology similar to that observed at NMDAassociated PCP site; 4-aminopyridine and PCP inhibit photoaffinity labelling of 80 kDa and 95 kDa protein by meta-azido-[3H]PCP

Bartschat, D. K. and Blaustein, M. P. (1988) in Sigma and Phencyclidine-Like Compounds as Molecular Probes in Biology (Domino, E. F. and Kamenka, J-M., eds), pp. 173-183, NPP Books; Sorensen, R. G. and Blaustein, M. P. (1988) in Sigma and Phencyclidine-Like Compounds as Molecular Probes in Biology (Domino, E. F. and Kamenka, J-M., eds), pp. 185-198, NPP Books

o-Binding site

PCP has modest affinity for this site (K, 0.5-3 ~M). Site is naloxone insensitive; labelled with high affinity by haloperidol, and (+)-3-PPP, di-O-tolylguanidine, (-)-butaclamol and (+)-SKF10047; MK801 is about half as potent as PCP at the o-site but about 60 times more potent at the PCP site

Quirion, R. et al. (1988) Trends Neurosci. 10, 444-446; Contreras, P. C., Contreras, M. L., O'Donohue, T. L. and Lair, C. C. (1988) Synapse 2, 240-243

benzomorphans (e.g. N-allyl-normetazocine and cyclazocine) and morphinans (e.g. dextrorphan and dextromethorphan), were shown to antagonize NMDA in a naloxone-insensitive manner 3. A subsequent series of SAR studies linked NMDA antagonism to the PCP receptor and to the behavioural properties of PCPlike drugs 3~. MK801, the most potent and selective of such drugs 7, has been used for modelling the structural requirements at this site s. I t b e c a m e readily apparent from neurophysiological and transmitter release studies that the actions of PCP, ketamine and related compounds were 'noncompetitive' and both use- and voltage-dependent 7'9. Similarly, the binding of PCP-like ligands is enhanced by NMDA receptor agonists 1°, reduced by competitive NMDA antagonists ~1 and, once established, not easily displaced in the absence of NMDA receptor agonists 12. The conclusion from all the above studies is that PCP-like compounds probably act within the ion channel

coupled to the NMDA receptor. For convenience, this site (which is distinct from o and opiate receptors, at which PCP also binds) is known as the phencyclidine or PCP receptor 13. Some of the compounds acting at this site are shown in Fig. l a. PCP-like drugs, benzomorphans and competitive NMDA antagonists have many behavioural properties in common; the potency of drugs in some behavioural paradigms correlates well with that in PCP binding and NMDA antagonism studies 14. Nevertheless there are sufficient differences to suggest that not all their actions are entirely due to reduced transmission at synapses subserved by NMDA receptors. For example, the competitive antagonist AP5 produced PCPlike catalepsy, stereotypy and discriminative stimulus effects in the pigeon 15, whereas there was only partial generalization between competitive antagonists and dissociative anesthaetics in rats 16 and monkeys 17. Thus, although there are certain

similarities between noncompetitive and competitive NMDA antagonists, it seems likely that the subjective effects of the two classes in humans will be different. None the less, the importance of NMDA receptors in cortical and subcortical processing of afferent information implies that NMDA antagonists will have profound effects on perception. Some PCP-like drugs may also induce behavioural effects by an action at a distinct non-opiate o-site, although at present the physiological function of this site has not been fully established [Ref. 18, and see F. C. Tortella et al. (1989) TiPS 10, 501-507]. It seems unlikely, however, to be directly related to excitatory amino acid pharmacology.

The glycine site HA966 and kynurenate are two other well established, but not very selective, NMDA antagonists which appeared not to have purely competitive properties. Understanding their mode of action awaited the discovery by


TiPS - February 1990 [Vol. 11]

found to act at the glycine site (Fig. lb). The most potent of these include DOQXA, 7-chlorokynurenate and MNQX (see Table II). Further, cyclopropyl substitution at the glycine 0~-carbon results in a potent but partial agonist, while cyclobutyl and cyclopentyl substitutions result in weak but selective antagonists. Structural requirements for activation of this glycine site have recently been modelled 22. In intact preparations, the selective glycine antagonists block exogenous NMDA- and NMDA receptor-mediated synaptic events, implying that glycine' site activation is an important requirement for functioning of the NMDA receptor-channel complex. Similarly, from electrophysiological and binding studies on isolated preparations, the actions of glycine antagonists suggest that occupation of the glycine site is necessary for NMDA receptors to produce channel opening 23'24.

Ascher and Johnson that submicromolar concentrations of glycine facilitated the action of NMDA in dissociated cell cultures 19. NMDA or glutamate facilitation of binding at the PCP site is also enhanced by glycine2°. This glycine site has a pharmacology quite distinct from the strychninesensitive glycine receptor which mediates synaptic inhibitions in the spinal cord and brain stem. Not only is its action resistant to strychnine, it is also mimicked by the D-isomers of serine and alanine and blocked by some cyclic analogues of glycine (Table II). In intact preparations, glycine and r)-serine have relatively minor effects on NMDA receptormediated events implying that in vivo this modulatory site is nearly fully saturated, although at this early stage such a conclusion may be premature. Antagonism of NMDA by HA966 and kynurenate, but not that by AP5 or ketamine, is reversed by glycine and D-serine, indicating that the mode of action of HA966 and kynurenate involves displacement of endogenous glycine21. Several other NMDA antagonists, including some quinoxalinediones, have now been

Other modulatory sites on the NMDA receptor The divalent cation Z n 2+ has also been shown to block NMDAinduced currents selectively but, in contrast to Mg 2+, does so in


a relatively voltage-independent m a n n e r as. Z n 2+ also reduces binding at the PCP site in a manner different from all other classes of NMDA antagonist. This action is mimicked only by high doses of some tricyclic structures such as desipramine and promethazine 26, although electrophysiologically the tricyclics show some voltage dependence. The selectivity of these compounds as NMDA antagonists has yet to be established in vivo. Polyamines may also regulate the NMDA receptor-ionophore complex, possibly via an intracellular site. The divalent polyamine putrescine is derived from the intracellular decarboxylation of ornithine and then converted to spermidine (trivalent) and spermine (tetravalent); reverse pathways exist. NMDA-evoked transmitter release and C a 2+ flux has recently been shown to be blocked by an ornithine decarboxylase inhibitor, an effect reversed by putrescine 27. Furthermore, spermidine and spermine, but not putrescine, were reported to increase [3H]MK801 binding; this effect was potentiated by glutamate and glycine28. Indeed recent structure-activity studies have








glycine aminocyclopropyl aminocyclobutyl HA966 carboxylic acid carboxylicacid O2N






N-allyl-normetazocine (SKF10047)








~ HO

CH3 ~



6,8-dinitroquinoxalinedione 7-chlorokynurenate (MNQX)


















argiotoxin636 OH

philanthotoxin 433

NH2(CH2)4NH(CHz)3NH z




Fig. 1. Structures of compounds with noncompetitive actions on excitatory amino acid receptors.


TiPS - February 1990 [Vol. 11]

TABLE II. Glycine antagonists

Antagonists 1-Aminocyclopentane- 1carboxylate(cycloleucine)

1-Aminocyclobutane carboxylate (ACBC)

Estimated K~( p M ) 650


1-Aminocyclopropane-1 -

carboxylate (ACPC)



competitive against glycineinduced [3H]TCP binding and [3H]glycine binding

Johnson, K. M., Snell, L. D., Jones, S. M. and Qi, H. (1988) in Frontiers in Excitatory Amino Acid

competitive against glycineinduced [3H]TCP binding

Hood, W. F., Sun, E. T., Compton, R. P. and Monahan, J. B. (1989) Eur. J. Pharmacol. 161, 281-282

partial agonist (ECso 135 riM) in [3H]MK801 binding

Marvizon, J-C. G., Lewin, A. H. and Skolnick, P. (1989) J. Neurochem. 52,992-994

Research (Cavalhiero, E. A., Lehmann, J. and Turski, L., eds), pp. 551-558, Alan R. Liss



competitive against [3H]glycine binding, poor selectivity with regard to kainate and AMPA receptor; endogenous metabolite of tryptophan

Johnson, K. M., Snell, L. D., Jones, S. M. and Qi, H. (1988) in Frontiers in Excitatory Amino Acid Research (Cavalhiero, E. A., Lehmann, J. and Turski, L., eds), pp. 551-558, Alan R. Liss; Kemp, J. A. et al. (1988) Proc. Natl Acad. Sci. USA 85, 6547-6550



potency and selectivity greatly

Kemp, J. A. et al. (1988) Proc. Natl Acad. Sci. USA 85, 6547-6550

improved over kynurenate 6,7-Dinitroquinoxaline-2,3-dione(DNQX)

0.8 }

6-Cyano-7-nitroquinoxaline-2,3dione (CNQX) 6,7-Dichloro-3-hydroxy-2quinoxaline carboxylic acid (DOQXA)


all poorly selective relative to


kainate and AMPA site; competitiye with respect to [3H]glycine binding

6,8-Dinitroquinoxaline-2,3-dione (MNQX)


structurally similar to DNQX but much more selective for glycine site

Sheardown, M. J., Drejer, J., Jensen, L. H., Stidsen, C. E. and HonorS, T. Eur. J. Pharmacol. (in press)

1-Hydroxy-3-aminopyrrolid-2-one (HA966)


structurally similar to the agonist cycloserine; competitive inhibition of NMDA-induced depolarization reversed by glycine; may be partial agonist

Fletcher, E. J. and Lodge, D. (1988) Eur. J. Pharmacol. 151, 161-162; Foster, A. C. and Kemp, J. A. J. Neurosci. (in press)

Indole-2-carboxylic acid


inhibition of NMDA-induced current overcome by glycine; little effect on the NMDA site; halogenated analogs somewhat more potent

Huettner, J. E. (1989) Science 243, 1611-1613

Kessler, M., Baudry, M. and Lynch, G. (!,989) Brain lies. 489,377-382

*Agonist K,j values in range 0.04-0.33 ~.M

shown the novel nature of this polyamine modulatory site and the noncompetitive antagonistic effect of putrescine on polyamineenhanced [3H]TCP binding (Fig. 2). The neuroprotective agent ifenprodil may also act at this site 29. The precise mechanisms and physiological significance of these effects o'f polyamines remain to be determined. A similar situation may exist with respect to the gangliosides for which reduction of NMDA receptor-mediated neurotoxicity and protein kinase C translocation has been claimed3°. Recently alcohol has been shown to modulate NMDA receptor function 31 but the full characterization and physiological implications have not yet been verified. Indeed, earlier reports 32 and some initial studies of ours suggest that alcohols are not selective as NMDA receptor antagonists.

The plethora of mechanisms by which NMDA receptor channel function (and subsequent second messenger events) can be modified provides exciting therapeutic avenues for the future. Differences in rate of access to the CNS, in duration, and in mode and site of action will, by analogy with the GABA system, be expected to produce drugs with different pharmacological spectra. Non-NMDA receptor--channel complexes The first article in this series showed that the pharmacological separation of quisqualate, AMPA and kainate responses is proving difficult. This raises the possibility that a single receptorchannel subtype, probably related to the AMPA binding site, mediates depolarizing responses to these agonists. This possibility receives support from some of the

work with noncompetitive antagonists, although far less is known about allosteric and channel blocking drugs affecting nonNMDA receptors. Barbiturates

Barbiturates reduce the actions of quisqualate and kainate about equally and to a greater extent than those of NMDA in both electrophysiologica133"34 and Na + efflux32 studies. It is presumed that this depends on a channelblocking action, since kainate antagonism is partly dependent on membrane potential 3s. Largely because of low affinity and poor selectivity between excitatory and inhibitory amino acids, interest in barbiturates as non-NMDA antagonists has not been maintained. A r t h r o p o d toxins

The well-known neuromuscular paralysis in invertebrates after


TiPS - February 1990 [Vol. 11]

oo m°°]

°ot, -7.5

-~.o -;.5




Log [drug]















03 c"


=.~ 4oo t=

"F, O.. 0


aoo 2oo

" 100 co 0 i0





% Control/[spermidine](~M) injection of certain spider toxins is due to blockade of the postsynaptic glutamate receptor channel complexes via a use- and voltage-dependent mechanism which indicates an open channel blocking action 36. The insect glutamate receptor is not activated by NMDA and its characteristics are more similar to the mammalian AMPA receptor type (although there are some important differences). Thus these arthropod toxins may offer a novel approach to non-~qMDA receptors, so their actions on mammalian neurons are creating a great deal of interest. Toxins from Argiope and ]oro spiders reduce excitatory potentials at synapses that are thought to be mediated by non-NMDA receptors 37. These toxins also reduce the effects of exogenously administered glutamate and quisqualate to a greater extent than those of NMDA 37. In a recent patch-clamp study 38, argiotoxin 636 selectively reduced NMDAinduced currents in cultured cortical neurons, whereas on trigeminal neurons in vivo philanthotoxin from the digger wasp proved to be a selective nonNMDA antagonist (Fig. 3). If these latter two results are confirmed, the structure-activity relationship

More importantly for differentiating subtypes of non-NMDA excitatory amino acid receptor, the arthropod toxins do not distinguish between the depolarizing actions of quisqualate, AMPA and kainate, which suggests that these agonists may activate receptors coupled to the same channels. The lack of effect of philanthotoxin on NMDA actions, and the reverse selectivity of Mg2+and PCP, confirms the view that channels activated by these receptors are pharmacologically distinct from those activated by NMDA. Although the pharmacology of the non-NMDA subtypes of glutamate receptor is in its infancy, there are exciting prospects in store and since these non-NMDA receptors are involved in many fast excitatory synaptic events in the CNS, drugs active at these sites may well have important clinical applications.

Fig. 2. Top: Effects of polyamines on specific [3H]TCP binding (as defined by 30 /~M PCm) in washed cortical buff)/coat membranes. [3H]TCP (5 mM) was incubated at room temperature for 2 h in the absence or presence of polyamine, m, N, N '-bis-(3-aminopropyl)1,3-propanediamine; ©, spermine ; @, spermidine ; & , 1,3-diaminopropane ; A, putrescine; r3, 1,8diaminooctane. ECso values range from O.78 +_ 0.04 #M (n = 3) for N,N 'bis-(3-aminopropyl)- 1,3propanediamine to 61 +_ 14#M (n = 4) for the partial agonist 1,3-propanediamine. Bottom: Eadie-Hofstee analysis of the inhibition of spermidine-induced [aH]TCP binding (0) by IO0#M (@) and 300#M (&) putrescine. The estimated K~ based on noncompetitive inhibition was 280 AiM. /See Sacaan, A. I. and Johnson, K. M. (1989) Neurosci. Abstr. 15.]

Other glutamate receptors Little is known of the pharmacology of the high affinity kainate, L-AP4 and 'metabotropic' subtypes of glutamate receptor. More functional studies are required with these receptor subtypes before the possibility of noncompetitive antagonism can be studied in detail. There are, however, some initial indications that L-AP4 and AP3 may be noncompetitive antagonists of quisqualate and ibotenate-induced PI turnover 39.

of the arthropod toxins will be particularly interesting, since these two toxins have marked structural similarities (Fig. lc). Whether the polyamine tail of these toxins interacts with polyamine and ganglioside sites of the NMDA receptor-channel complex remains unclear; gangliosides block some of the actions of kainate 3°. PhTx 60=

.tiT_ o°

i m














i m



1 rain Fig. 3. Effect of philanthotoxin on responses of a single brainstem neuron in a pentobarbitone-anaesthetized rat to the electrophoretic ejection of NMDA (N, 30 nA), quisqualate (Q, 24 nA) and kainate (K, 32 nA). Philanthotoxin (Ph'rX) ejected with a current of 5 nA reduces the increase in firing rate to quisqualate and kainate approximately equally, but does not reduce the firing rate to NMDA. Recovery is shown 35min afterthe ejection of PhTX. [See Jones, M. G., Anis, N. A. and Lodge, D. (1989) Neurosci. Lett. (Suppl. 36), S25.]

TiPS - February 1990 [Vol. 11]


Acknowledgements David Lodge is supported by grants from the MRC and Wellcome Trust and Ken Johnson by grants from the National Institute on Drug Abuse. References 1 Monaghan, D. T., Bridges, R. J. and Cotman, C. W. (1989) Annu. Rev. Pharmacol. Toxicol. 29, 365--402 2 Johnson, K. M., Snell, L. D., Sacaan, A. I. and Jones, S. M. Drug Dev. Res. (in press) 3 Lodge, D. et al. (1988) in Excitatory Amino Acids in Health and Disease (Lodge, D., ed.), pp. 237-259, John Wiley and Sons 4 Aram, J. A. et aL (1989) J. Pharmacol. Exp. Ther. 248, 320-328 5 Snell, L. D. and Johnson, K. M. (1985) J. Pharmacol. Exp. Ther. 235, 50-57 6 Zukin, S. R., Brady, K. T., Slifer, B. L. and Balster, R. L. (1984) Brain Res. 294, 174-177 7 Wong, E. H. F. et al. (1986) Proc. Natl Acad. Sci. USA, 83, 7104-7108 8 Manallack, D. T. et al. (1988) Mol. Pharmacol. 34, 863-879 9 MacDonald, J. F., Miljkovic, Z. and Pennefather, P. (1987) J. Neurophysiol. 58, 251-266 10 Loo, P. H., Brunwalder, A. E., Lehmann, J. and Williams, M. (1986) Eur. J. Pharmacol. 123, 467-468 11 Fagg, G. E. (1987) Neurosci. Lett. 76, 221-227 12 Kloog, Y., Nadler, V. and Sokolovsky, M. (1988) Biochemistry 27, 843-848 13 Quirion, R. et al. (1987) Trends Neurosci. 10, 444-446 14 Snell, L. D. and Johnson, K. M. (1988) in Excitatory Amino Acids in Health and Disease (Lodge, D., ed.), pp. 261-273, John Wiley and Sons 15 Koek, W., Woods, J. H. and Ornstein, P. (1986) Life Sci. 39, 973-978 16 Willetts, J. and Balster, R. L. (1988) Neuropharmacology 27, 1249-1256 17 France, C. P., Woods, J. H. and Ornstein, P. (1989) Eur. ]. Pharmacol. 159, 133-139 18 Sonders, M. S., Keoma, J. W. F. and Weber, E. (1988) Trends Neurosci. 11, 37-39 19 Johnson, J. W. and Ascher, P. (1987) Nature 325, 529-531 20 Reynolds, I. J., Murphy, S. N. and Miller, R. J. (1987) Proc. Natl Acad. Sci. USA 84, 7744=7748 21 Fletcher, E. J., Millar, l- D., Zeman, S. and Lodge, D. (1988) Eur. J. Neurosci. 1, 196-203 22 Fletcher, E. J., Lodge, D. and Beart, P. M. in Glycine Neurotransmission (Storm-Mathisen, J. and Ottersen, O. P., eds), John Wiley and Sons (in press) 23 Kushner, L., Lerma, J., Zukin, R. S. and Bennett, M. V. L. (1988) Proc. Natl Acad. Sci. USA 85, 3250-3254 24 Kleckner, N. W. and Dingledine, R. (1988) Science 241,835-837 25 Westbrook, G. L. and Mayer, M. L. (1987) Nature 328, 640~43 26 Reynolds, I. J. and Miller, R. J. (1988) Br. J. Pharmacol. 95, 95-102 27 Siddique, F., Iqbal, Z. and Koenig, H. (1988) Soc. Neurosci. Abstr. 14, 1048 28 Ransom, R. W. and Stec, N. L. (1988) J. Neurochem. 51,830-836

29 Carter, C., Rivy, J-P. and Scatton, B. (1989) Eur. J. Pharmacol. 164, 611-612 30 Favaron, M. et al. (1988) Proc. Natl Acad. Sci. USA 85, 7351-7355 31 Lovinger, D. M., White, G. and Weight, F. F. (1989) Science 243, 1721-1724 32 Teichberg, V. I., Tal, N., Goldberg, O. and Luini, A. (1984) Brain Res. 291, 285-292 33 Simmonds, M. A. and Home, A. L. (1988) in Excitatory Amino Acids in Health and Disease (Lodge, D., ed.), pp. 219-236, John Wiley 34 Collins, G. G. S. and Anson, J. (1986) Neuropharmacology 26, 167-171 35 Miljkovic, Z. and MacDonald, J. F. (1986) Brain Res. 376, 396-399 36 Jackson, H. and Usherwood, P. N. R. (1988) Trends Neurosci. 11, 278-283 37 Saito, M. et al. (1989) Brain Res. 481, 16--24 38 Priestley, T., Woodruff, J. N. and Kemp, J. A. (1988) Br. J. Pharmacol. 97, 1315-1323

39 Schoeppe, D. D. and Johnson, B. G. (1989) J. Neurochem. 30, 1865-1870 AP3: amino-3-phosphonopropanoate AP4" amino-4-phosphonobutanoate AP5: amino-5-phosphonopentanoate

• In next m o n t h ' s TIPS, Anne Young and Graham Fagg discuss radioligand b i n d i n g experiments in the s t u d y of excitatory amino acid receptors. New, more selective radioligands are n o w available to map receptor s u b t y p e distributions in the brain in normal and disease states, to s t u d y allosteric interactions at the N M D A receptor and to develop novel therapeutic strategies.

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Noncompetitive excitatory amino acid receptor antagonists.

In the first article in this series, Watkins, Krogsgaard-Larsen and Honoré outlined the structure-activity requirements at the receptor sites for exci...
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