- Email: [email protected]
Taking stock of cognition enhancers
TiPS- December 1991[Vol. 121
456
Taking stock of cognition enhancers Martin Sarter An increasingnumber of structurallyheterogeneous compounds,which may act via very diffrrenf categories of neuronulmechanisms,haw been proposed to fucilifate attentional abilities and urqufsftion, sforuge and retrieuuI of information,and/or to attenuate the impuirmentsof such cognitivefunctions associatedwith age or dementia. In this article, Martin garter briefly reviews the data on putative cognition enhancers and examines fbe possible buses for the discrepancy between preclinkul predictions of efficacy and the fact that uneqniuoculdemonstrationof drug-inducedcognition enkuncementin humans has only rarelybeen reported. Previorrs,preclinicuIresearch stmtrgics appear to have focused on the demonstrutionof drug effectsin u wide variety of tests oj uncertain validity, ruther thun on &termination of the specijic psychologica! and neurobiologicul proresses uffected by putatiur cognition enhuncers.Some criteria ure proposed for ccaiuating Be validity ofpnclinicul tests for cognition enhancers. The efficacy of prototype compounds of majorclasses of neuropsychiatric drug treatments has heen discovered almost unintentionally. For example, the neuroleptic efficacy of chlorpromazine was discovemd while Lahorit was investigating antihistamines for the treatment of surgical shock in 1951, and iproniazid was found to enhance the mood of patients being treated with this drug for tuberculosis. However, cognition activators, cognition enhancers, nootropics or intelligence boosters have yet to emerge from serendipitous discovery. Strategies for ffnding nootropicdrugs have attempted to develop drugs that interact with various neuronal mechanisms that are thought to underlie cognitive abilities and dysfunctions, including dementia. Given the fact that these hypotheses themselves are subject to intense scrutiny, and given the absence of any consensus with respect to animal models, testing procedures and clfnical goat symptoms, it comes as no surprise that the demonstration of a wide variety of effects of putative cognition enhancers has
dominated preclinical research activities. The specific neuronal and psychological mechanisms involved in drug-induced cognition enhancement have rarely been studied. Previous reviews and several symposia on cognition enhancers have ilhtatrated both the resulting hekqeneity ofmaearch, and the diffkuhy in determining the validity of evidence suggestfng
ition enhancedrug-induced ment”. A brie T survey of two major classes of putative cognition enhancers, the ‘nootropics’ and the cholinomimetics, and of some more recent compunds (see below), confirms this state of affairs. Thenootropio In contrast to the conventional classification of psy&otqic ccnnpounds in which drugs are named according to symptoma relieved (for example ‘anti-f), the term ‘nootropic drue refers to the drugs’ presumed mechanism of
CH,CH,
vinpocetine action as AIt of the so-called ‘telencephB ic hypothesis’ or&inally propow! by Giurg&. This hypothesis ad&saas effects of nootropics on idiorynaHaasy defined brain funct&xu that appear to be difficult to test. For exam@, noot@caarepsopoa&tu&anee cortical vigikca, a tekm@dk functionalsekctivity;th*gmpar-
titularly effective in maWing deficient higher newoua activity; and they do not induce direct retfcular, limbic or other subcortical eve&.
TiPS - December
1992/Vol. 121
The effects of nootropics listed in Table I suggest an almost ubiquitous potential for facilitating various types of behavioral ability, for attenuating the detrimental effects of diverse treatments and for stimulating numerous neurochemical plocesses. Nootropics have been proposed to facilitate information acquisition, consolidation and retrieval, and ‘it is presently unclear which effect, if any, predominates*. Table I and the above quote illustrate that the research on nootropics has focused on the demonstration of efficacy in a be number of diverse tests. This strategy has generated a considerable amount of data; however, the significance of these results in terms of predicting This problem can also be illustrated by a discussion of the effects of the pyrrolidone derivative DM!?M49.Thiscompoundhasbeen repor&d to attenuate the amnesic effects of two drugs with conflict~~~~~ which facilitates the effects oi GABA, and the GABAA receptor bicuctdline. The efficacy Cattenuatetheamnesia caused by chlordiazepoxide was antagonized by bicuculline. Fu&enmne, this compound was to ameliorate the amnesic 82 ef&z? of cidoheximide, scopolamine, hemicholinium-3, basal -rain lesions, ekctroconvulsive shock, picrotoxin and ethanol (see Ref. 7). However, the specific behavioral and neuronal mechanisms involved in the drug’s effects and the dinical potential of such a ‘universal attenuator’ remain undear. Based on such preclinical findings, an impressive number of indications has been proposed for
tations of the predictive validity of preclinical data. The failure to determine the validity of the different behavioral paradigms (see Box) and of animal models used for the characterization of ncotropics may represent a major basis-for incorrect predictions of clinical efficacy.
“\ ,..JrCH,C~C”
,-, CnACH, o-selegiline
the nootropics (see Ref. 10). However, results flwn umhuiied dfnkal MaIs (which inch&d patients suffering from senik demenHa”*12, akohol organic disorder’) or age-associated cognitive dysfunctions”) indicate profound limi-
Cognition
enhan-nt
ChOhWdllld
Via
IMC-
Unlike the research on the nootropics, the search for cognition enhancers that operate via cholinergic mechanisms has been fostered by a rationale that was derived
zxhbasic
from
newopathdogical
psychobiological reDiverse experimental appro&hes have consistendy
suggested that the cognitive dysfunctions associated with normal aging or with degener&ve disorders are based on disruption of cholinergic functions’? The cholinergic hypothesis has, however, not been fully supp@ed by basic reseti on the functions of theforebrainchdinergicsystemor by clinical data, and thus has come under attackn*16. l!oosting this dialectic process, Fib&r” recently umduded that programs aimed at develop@ chobxgic pharmacothempies for the cognitivedeficitsinsefdledementiaare based ‘more on faith than on established f&s’. Indeed, there is littk knowMge of the specific cognitive fimctions that are dependent on forebrain choliergic
TiPS - December 1991/Vol. 121 I
The diffkulties of successfully predictingthe clinical etXcacy
putative cognition enhancers appear k~ely due to me uncertainty about the validity of animal models and
of
behavioral methods (see Ref. 1 and main text). since the mnal mechanisms that mediate cognitive functions are Pooay u&Mood, and as there is no consensus about the spe&ic pslrrhobgicsl components of tha w or dementiaassociated impairmbs In cognitive abilities, a straight validation of pmdinical test systems forcognition enharwm is not possible. Howwer, similar to WiW2 WabtiOn of animal modeis of depmssive disorders, a set of general validation criteria can be applied to determine the rig nificsnce of the various animal models and behavioral tests.
forexampkautomaticvemus
Coasbnct t&f&y An animal mode! may show good constructvalidity if it reflectsetioiogicalor other theoretical
;iptiuns about the symptums to be mudelled. Some of the most relevant exsmpks rue animak with cholinergic hypafwtb that has been induced surgicallyor phkmacologkally. Ibe modeis have been considered to possess
goadamstructvalidityastheyarebasedonthehypothmis itive impsirments in aging snd dementia are s that the resuh of“gp: fun&ma1 or structural dedine in forebrain cholinergicsystems. Howevar, the construct validity of thsss madebhasbsencriticiaedandauatificdu.Forexarnnk. aredueto~c&dtadeofmuscsrinica&khohm teceptors,itisthelossofpmsyn+icchohne@neumns thatmaympresentamajorneumnalcorreiateofdementia. Asecc&exampleistheextenttowhichthebahsviorsl unpdrnrmtr produced by exdtoWc acid-induced bass1 forebrain lesions are due to choiinergiccell loss? GOdC!OMUCtValidityd~snimrlmodeliS~
but tn&ficient w a b&s for generating widence of cognitive arhmamcnt. For example,attributing predictive validity(seebeiow)toatestsuchasantagonismofthe effectsof -tally induced choiinergic hy@unction, is@stifW(67diffwentdmgshsvebeenreporkdto attenUe behavioral effectsof acopolamint’).Thewnstruct
systems, and current animal models of the behavioral consequences of cholinergic hypofunction are of limited validity. However, since changes in cholinergic activity correlate with dementia, and since the behavioral pharmacology of cholinergic drugs has consisteutly suggested that the cholinergic system is prominently involved in cognitive processes, the hypothesis that cognition enhancement is mediated via stimulation of choiinergic activity remains attractive’s. Meanwhile, the discrepancy between preclinical efficacy of chohnomimetics and discouraging results from clinical trials indicates that caution is necessary. Table II lists putative cognition enhancers thought to act via cholinomimetic mechanisms, and indicates whether tire/ have &en
tested in clinical settings. The data from these trials suggest that muscarinic acetylchohne receptor agonists do not produce beneficial cognitive effects, and whilecholinesterase inhibitors did have effects,
indeioxazine they were considered ‘of heuristic rather than clinical significance”6 (see also Refs 7 and 19). Inappropriate pharmacokinetic properties and inadequate clinical pmtocob have been suggested to contribute to this lack of effica$‘. Also, muscarinic agonists and cholinester- inhibitors maydisrupt the patterning of cholinergic trans-
mission; however, it has been hypothesized that patterning rather than the absohrte amount of acetylcholine, is critical for signal pmcessit$‘. TheAxe, the potential of pmcholinergic mecha&ms for mediating cognition enhancement cannot be judged on the basis of the effects of conventional cholinomimetics. This may be relevant to the action of nicotine, which improves attentional processing in demented patienhll, since the extent to which this effect is due to release of acetylchohne is unknown
Modulatin the activity of presynaptic cho! inergic neurons and thereby preseming physiological signal transmission has been considered an advantageous
EPS - December 2991IVol. 121
459
kvant to the primary dysfunctions in human amnesia and
rmt a ta+ for drug-induced cognition enhancement. Determination of the face validity of a behavioral parap is a chaUen@g exercise, requiring sophisticated and A. --l-uJRP “1 A ,I...M~l t.“UI~9cl113 _U”_..k ,115 ~..“..&cL. *ysrun LL_.‘ VSIIY..wSU a test procedure. Contradictorymsults were Wned with ckmidine in aged nonhuman primates that
m &ted in tasks for recent spatipl mem~ry~~, which + aEke from a concephralbut not a hxhnical point of ew - indicating the potential gravity of this problem. W
t&&y An imxeasing number of putative cog&on enhancers are being tested in healthy humans and in @ous dinical conditions. Paradoxically, the drugs that em identified by, for exampie, passive avoidance tasksbut iMtoehowe~~indinialbiJs,hhrs~rrsultedina aaring re-evahzation of the (face and construct) validity !dab w using thii pamdigm. The value of fzlinical * is aiso shown by the discqmq in the effects of mddine (eae above). As the p&i&on that ‘admneqic @sta might &niiarly be helpful for pat-c@ with lsMner% diws~e’~ has not been confirm#~“, greater IMitymaybea&&utedtothoeeellperimental~ ~txsveal donidine-induced enhancement of 0
0
cl
matton of a single aspea of validity (face or conntct)ofananimalmodelorabehavioraitestpmcedun to ensure that the results will have ‘. However, a combination of both face x z
were examin& in scopolamine-treated primates !!!!!% 8-r I -r, .ld.“Yl -_ b..L. I” n&h- -, v -u,?? -UII “I uM=. “Y&Y=, ~~~~emplbycd an animal model of Hmited but
defined construct validity, and a behavioral paradii that permits variation of the cognitive task demands. physostigmine attenuated the effects of sqolamine but not the similar effects of eithez agins extended retention in&v*, __ ._ -_-_A uw --A Ucnl~Icc ~-_-._.a --_L1__._ --- L.~_ “I AlA.-A^YIDUHUVII. M S”mvcIs1R -- .~
sensitive to inte&ence during retmt& intuvals~‘the results by Rutmiak et al.” oredict that in-induced amnesia-will hot be atten&ed by physost@ine, and that scopolamine does not model thii situation. This type of research, which aims at identifying the specific cognitive defects impkmmted by an animalmodel,and de&mining the exact psychok+) nature of a drug effect, will significantly increax the predictive validity of preclinical data.
References 1 Sarter,M., Hagan,J.J. and Dud&e&o, P. pSychophnrm~c&gy (in pcsa) 2 Wittner, P. (Ml6) f’#yd+armaco&y 83,1-16 3 Hagan.].J.andMmTi&RC.M.(1968) the Aging Nwvow Systm Ufmdbwlr of 20) kmsen, I.. L, Ivemen,S. D. and Snyder,S. H., eds), pp: 237-323,PlsnumPress 4 Fib@, Ii. C (1991)Tmdr NeuraJn’14,~223 . 5 Robtdna,7. W. d rl. (l9B9)NCU&M 2s.337-352 6 Morris, R. G. ht. (1%) in Nrmmbidqy of LeaendMemory (Lynch, G., ffiugh, J. L and Wein-, N. M.. eds), PP. 119-124,Guildbrd Ress 7 Heiav,G. A. (1964)Mrd. Rcs.Rev.4, Sx-!i58 8 Olton, D. S. and w, A. L (MB) Neumbiol.Aging9, 46M74 9 Iaquierda,1.(19&) Ten& P/wnwol. !ki. 7,47U77 10 A.rnsten,A. F. T. and Goktmm-Rakic,P. S. (1985)S&ace 7.30, 1273-1276 11 Bartus,R T. and Dean. R L (MS) Ncumbiol.A& 9, Iop-lll 12 ~“;;R.$,an, M. J. and Downs,D. A. (1966)Dnig Dcu. 13 M&r, ‘E.et al. (1969)Arch.Neural.46,376-378 14 Scklegd,J. cl al. (lm Cfin.Neuropbarmafm. 12.174-126 .c .1 .1 I *._ R. n., IF, c 3. I.,t c1-l-I c~nu, .m.. J.1 iid 12 ~..-I_,_ mupnlu. iv. .a m. ,.,. 1_--, Ivmm, S. D. (1991)Behm.BruinRcs.43,1-6
properties of most of these cominterfere with potential beneficial effects on cognitive processes, some benzodiazepine re,cH*lcn,l,cwJ+li* :: ceptor ligands appear to combine properties typical of inverse agonists (in terms of inhibition of CABAergic transmission and facilitation of behavioral functions) with the abstince of proconvulsive -- a”rWgenlc __..:_-__:_ _..-_-_C___^_ or prupWun I^_ (VTCYell with anticonvulsive effects; see listed in Table II may involve MDL26479).As the inverse agonisttranssynaptic mechanisms. Inlike effects of these compounds verse agonists at the benzoappear most obvious on behavioral diazepine receptor are proposed facilitation, they have therefore to allow a rigorous test of this bern termed benzodiazepine restrategy. Specifically, it has been ceptor-selective inverse agonists%. hypothesized that these comThe biochemical and behavioral pounds stimulate acetylcholine reproperties of the @-carWine lease in the forebrain via negative ZK93426 have previously beenreallastcrlc modulation of GABAviewed*‘. Table III summarizes ergic transmission at chollnergic the data on a novel prototype cell bodic~*‘~. While the procompound that appearsto stimuconvulsive and p4blyanxiogenic
alternative to traditional cholinomimetld”. Some of the acetylcholine-releasing compounds
pounds
late acetylcholine anabolism as a result of benzodiazepine receptor-mediated inhibition of GABAergic transmission, the triazole MDL26479 (Ref. 25). Both ZK93426 and MDL26W9 increase forebrain &olinergic transmission (Reb 25, 26; j. A. Miller rt ul., unpublished) and
acecliiine the effects of experimentally induced disruption of cholinergic transmission (Ref. 21; M. garter cf al., unpublished). However, the extent to which drug-induced behavioral facilitatIon depends on the increase in choline&c activity is unknown. attenuate
TiPS - December 1991/Vol. 121
460 TABLE III. Phwt’naWqif3f
pmpertias of MM26479 Et&l
Test Diw
Longng
of [W)fbmazenil binding
potentialion in h@pocampal
spaw defay6d aflemabon piwmance in rals(d&Jys:2-32swxlds) .Sco@amina (0.03 ~0.1 mg kg-$ndwed fmpa#manl h spatiaf delayed afferfwion we
EDw = 0.22+0.05 mg kg-’ hp. in viva, mou5ecwfex coltex: 133% ilwease hippccamW:~ChfWP anfago&m(fntefmsofB,;ncwoflhe lmabnen~~~ hfippocapuscA1: 224% fncreaae hippocMprschu:216%inaesse dWWBgyius:WJChMge noeffecfs(l-3Wngkg-‘:Ef&,,~ fbmazw: 5.83fng kg-‘) nOellee6(upW?gWJkg-‘) noeffectsiuplo3omgkg-‘) increased ampfifuda of basaf population SW(lMqru) no effecfs (0.10-6.25 mg kg-‘) anlagonism
From Ref. 25: J. A. Miller efaf., ~npubilShed:M. Sable?etaf.. Unpbffshed.
cognition-enhancing As the properties of ZK93426 have been confirmed in intact human volunteers*‘, transs);napticaily induced stimulation of cholinergic activity appears to represent a promising neuronal mechanism for druginduced cognition enhancement. Drugs acting via non-cholinergic Table N indicates the diverse non-cholinergic mechanisms that have been considered targets for the induction of cognition enhancement. Although most of the compounds listed in this Table have not been studied extensively, beneficial effects on mental abilities m humans have been consistently predicted but rarely confirmed 5; human trials (see, for example, Reb 28 and 29; but them are promising effects in aged or demented humans reported for sabeluzoldO and selegiline3rX). Thus, the discrepancy between the optimistic predictions based on animal behavioral pharmacology and the dissatisfying findings in humans (a picture that also emerged from the discussion of nootropics and cholinomimetics) again su ests that conclusions fromp z* nncal research strategies and methods are invalid (see Box). =I
@
0
Resealh on cognition enhancers has focused on the demonstration of a wide range of drug effects in diverse behavioral tests and animal models, probably reflecting
the fact that ‘standard’ compounds are not available. Furthermore, the lack of knowledge about ‘pharmacologically accessible’ neuronal mechanisms that mediate complex mental abilities, and about the SpWifk psychological abilities that are potentially subject to pharmacological enhancement, has contributed to an uncritical use of behavioral tests with limited or unresolved validity (in terms of examining relevant cognitive func-
tions). Consequently, a relatively high number of false-positive cognition enhancers has been detected. Some criteria and procedures that may be useful for determining the validity of such tests and models have been proposed (see Ref. 7 and Box). In spite of these problems (which are possibly typical for a juvenile science), promising new compounds have emerged as putative cognition enhancers. several studies in human
milacemide volunteers and in patients with age-associated cognitive dysfunctions or dementia have confirmed that drug-induced cognition enhancement is a therapeutic possibility. Confirmation and psychological specificathm of the cognition-enhancing prqrties of promising drugs would provide the necessary tools for basic and applied research on the neuronal mechanisms of cognitiwpm03ses. Acknowl+stsenb The Box is based on a paper (Psychopkanacofogy, in press) that is co-authored by Jim Hagan (SmithKline Rae&am, Harlow) and Paul Dudchenko (Ohio State
TiPS - December 1991 Md. 121
University). I am indebted to them. I am grateful to J. Bruno and P. Dudchenko for discussions on earlier drafts of this manuscript. Research was supported by the US Public Health Service grants NIA AGlOl73-01 and MH 46869. OlAl, The Ohio Department of Aging (ADR-l-90), The American Federation for Aging Research, and the Sandoz Foundation for Gerontological Research. Referawes 1 Crwk, 2, &rtus, R., knir, S. and cmhon,
S., ads (1966) Treatmrnf De-
Strategtes r&pmrt DisrHe,Ma?kpwley~.
fir
Akhtimer’s
2 Mow. H., Davis, R., Schwarz, R. D. and Ganuu, E. (19&l) Med. Res. Rcu. 3, 353-w 3 Pumdt, R. D. (198s) Tr&s Phanoacol. 56-i.10.3-6 4 Ruhhins, T. W. (19&a) Nufurc 336, 207-2txi -_. -_ 5 CiurBea, C. U. (19S2) Drug Dm. Rn. 2, 441-446 h Nlcholaun, C. D. (1990) Rythophanna. cofogy101, 147-159
7 Sarter, hf., Ha~im, 1.1. and Dudchanko, P. Psycho@arwacolo~y(in press) 8 Ha~an, J.J.md Monk It.G.M.(196s) In PayckoPbanaacofog of thr Agiag Newour System fifa r&o k o( Psychopharmacology, Vol. 20) (Iwrmen, I.. L., Iveraen, S. D. and Snyder, S. H., eda), pp. 237-323, Plenum Press
9 Nabeahima.
T.,
Toyama,
K. and
Kameyama, 7: (1990) Phatwcrol. Biochew. B&PI). 36. -236 10 Ba~na, C. A., I’omam, N., Cmok, T. and Gemhun, 5. (1986) in Treatment
Ddopmrnt Stratqie for Ahhrimrr’s Dfsease Oook, T., Sartus, R.. Ferris, S. and Gemhan, S., edr), pp. 55%X Mark Powkv Assoc. 11 Claus, ). J. ;t of. (1991) Nrrmfogy 41, 570-574 12 Ctuwdon, J. H., Corkin, S., Huff, F. J. and Rosen, T. ). (19B6) Ncarobiol. Aging
461
15 Bartus, R. T., Dean, R. L., Pontacorvo, M. J. and Rkker, C. (1986) in Memory Dysfuncfious:Iufcgmtion of Animal and Hawn Rewarch from CIinical and Preclinical PrrspCrrmes(Cltut~, D., Camzu, E. and Corkin, S., ads), pp. 332-35& NY Academy of Sciences 15 HaBan, J. J. in Anti-dementia AgentsRcscarck and Prospects for Tbcrapy (Nichulscm,C. D.. ed.). Academic Press (in press) 17 Fib@, H. C. (1991) Tends Nc~rraxr. 14,
2%223 18 Sartar, M., Bruno, J. P. and Dudchenko, P. (1991) Twtkr Neuroscf. 11,484 19 Becker, R. E. and Ciacubini, E. (19B5) Drug Dro. Rcs. 12,163.195 20 Bartus, R. T. (1990) 1. Am. Crriatr. 5oc. 3BbSB695 21 Sarter, M., Bruno, J. P. and Dudchenku, P. (19%) Psychophanoacofogy 101, l-17 22 Sahakian, B., Jones, C., Levy, R.. Gray, 1. and Warburtun, D. (19B9) Br. 1. ky-
chialry 154, 797-SOO 23 Salter, M., Schneider. H. H. and Stephens, D. N. (1988) Trruds Neamsci. 11.11-17 24 S&r,
54. (1990) Eur. 1. Pbom~acol.177,
155-162 25 Milkr, J. A. and ChmieIewski. P. A. (1990) 5or. Nrrroaci. Abstr. lb, 91.11 26 Bruno, J. P., Moora. H., Dudchenku, P. and Sarter, M. in Tbc Trcatmrnt ~1 Dzncntias: A Nrw Cramtion of Progress
(Mayer, E. M., Cm,
F. T. and Simg
kins, J. W., eds), pknum Press(in press) 27 Duka, T., Stephena, D. N., Krause, W. and Domw, R. (1907) Psychophawaacology93,421Xi7 28 Markstein. R. (1969) Eur. Nrurof. 29 ~Suppl.), u-4 29 F;rndpg, Tz (1990) New Eql.
Xl &II:&,
<.
H. C., Tritsmans, I., C., Amery. W. K. and Janssen, P. A. J. (198R) Psychophamacology94,52-57 31 Tariot, P. N. rt al. (19S7) Psychophmacology9L4S9-495 32 Man@, A. cl al. (1991) Eur. Ncuml. 31, 1MlW Idrikowski.
BDwllsc (s)-2,S.dimethyl-1,3-dioxa.Burrpimt4.5&cana(Z)-2-butenedioate CBBu6733r2-methyl-or-eaocryph Cl979! o-l2#5~tet&ydr&IZyI.~ pyrfdlne arhuaaI~DmethyIoxime mcmuhydmchbrI& DM93Mt N-(2,&dImethyi.phenyB.2-(zuau-l-pyrruRdinyl)-acatamide I)llpr)6e 33bfs(4pyrindinytmethI;l)-lphenyIindoIin-2-cme B2S2&(2).23.dihydru-5,6-dimethaxycthmy2-(Il-(phmymwUlyl~4-pi~~~inyl]methyl]-Hi-inden-1.une Fl
Hoe17513,S-dbnethyi4phenyl-S&7,& tetrahydm-pyrazow3*4.w5)diaaapim.1H,4H-5,7-diie Hpo19. (*I-9-amino-1,234. tetmhydmacridin-l-d-maieate 1CS%593&(k-tmpanyI)-lH.;adole-3~ carboxyIicacid eater JOl7tN (+)_N-cyc~yl-methyl-Nmethyl-1,4.diphenyI-l-yi-but+en-l-
ylrmine hydmchbridc MClZt?It I-@-benr/lpfwnoxy)-Nmethylbutylaminehydmcbbride MM161798S-(3-Suompbenyl~.2Adbnethyl.3%1,2#ria&-3.tbi~ NIWII: 9-amino-2.3~$,7#-heaahydm. llf.cy&panta~b]quinoRne munuhydrate hydmehknide
(45)-decan-1,3-dimte-Iwdmhmmide
SDZRNA7Is: (-)N-ethyl-N-methyl-O’-(l”dimethylaminu)-ethyi)-pbmyi-carbamata hydrogan(rtirate SDR2lambf (-)12-mathyl-spiru-(0 dimtuIan-4,4’l-l’-methyI-piperidinhydvfenmaIata
SMlWSW-~illO-8-tlUlU-l~,4. g$z$-g~;~~ (4.phenylbutyt)pho@inylloxyWc=o. newl-2-wdim
-fJ2ai-rleaaharbr
7,~27b I3 Bamaa, C., Miller, C, Gunther, V. and Ileiuhhacker, W. (1987) Pro& NearoPs~ychoPharwacol. Biol. Psychiatry 11,
v-9-M: vaI-Rn-vaI-Glu-AIa-vaI-Asp.pru. Met
729-737 14 Reiabeq, C. et rl. (1982) Dn18 Duu. RES.
~~~~~hyl~
2,475-480
YMl467& Nq[($~2-
carbulhw-3-c-
456
Taking stock of cognition enhancers Martin Sarter An increasingnumber of structurallyheterogeneous compounds,which may act via very diffrrenf categories of neuronulmechanisms,haw been proposed to fucilifate attentional abilities and urqufsftion, sforuge and retrieuuI of information,and/or to attenuate the impuirmentsof such cognitivefunctions associatedwith age or dementia. In this article, Martin garter briefly reviews the data on putative cognition enhancers and examines fbe possible buses for the discrepancy between preclinkul predictions of efficacy and the fact that uneqniuoculdemonstrationof drug-inducedcognition enkuncementin humans has only rarelybeen reported. Previorrs,preclinicuIresearch stmtrgics appear to have focused on the demonstrutionof drug effectsin u wide variety of tests oj uncertain validity, ruther thun on &termination of the specijic psychologica! and neurobiologicul proresses uffected by putatiur cognition enhuncers.Some criteria ure proposed for ccaiuating Be validity ofpnclinicul tests for cognition enhancers. The efficacy of prototype compounds of majorclasses of neuropsychiatric drug treatments has heen discovered almost unintentionally. For example, the neuroleptic efficacy of chlorpromazine was discovemd while Lahorit was investigating antihistamines for the treatment of surgical shock in 1951, and iproniazid was found to enhance the mood of patients being treated with this drug for tuberculosis. However, cognition activators, cognition enhancers, nootropics or intelligence boosters have yet to emerge from serendipitous discovery. Strategies for ffnding nootropicdrugs have attempted to develop drugs that interact with various neuronal mechanisms that are thought to underlie cognitive abilities and dysfunctions, including dementia. Given the fact that these hypotheses themselves are subject to intense scrutiny, and given the absence of any consensus with respect to animal models, testing procedures and clfnical goat symptoms, it comes as no surprise that the demonstration of a wide variety of effects of putative cognition enhancers has
dominated preclinical research activities. The specific neuronal and psychological mechanisms involved in drug-induced cognition enhancement have rarely been studied. Previous reviews and several symposia on cognition enhancers have ilhtatrated both the resulting hekqeneity ofmaearch, and the diffkuhy in determining the validity of evidence suggestfng
ition enhancedrug-induced ment”. A brie T survey of two major classes of putative cognition enhancers, the ‘nootropics’ and the cholinomimetics, and of some more recent compunds (see below), confirms this state of affairs. Thenootropio In contrast to the conventional classification of psy&otqic ccnnpounds in which drugs are named according to symptoma relieved (for example ‘anti-f), the term ‘nootropic drue refers to the drugs’ presumed mechanism of
CH,CH,
vinpocetine action as AIt of the so-called ‘telencephB ic hypothesis’ or&inally propow! by Giurg&. This hypothesis ad&saas effects of nootropics on idiorynaHaasy defined brain funct&xu that appear to be difficult to test. For exam@, noot@caarepsopoa&tu&anee cortical vigikca, a tekm@dk functionalsekctivity;th*gmpar-
titularly effective in maWing deficient higher newoua activity; and they do not induce direct retfcular, limbic or other subcortical eve&.
TiPS - December
1992/Vol. 121
The effects of nootropics listed in Table I suggest an almost ubiquitous potential for facilitating various types of behavioral ability, for attenuating the detrimental effects of diverse treatments and for stimulating numerous neurochemical plocesses. Nootropics have been proposed to facilitate information acquisition, consolidation and retrieval, and ‘it is presently unclear which effect, if any, predominates*. Table I and the above quote illustrate that the research on nootropics has focused on the demonstration of efficacy in a be number of diverse tests. This strategy has generated a considerable amount of data; however, the significance of these results in terms of predicting This problem can also be illustrated by a discussion of the effects of the pyrrolidone derivative DM!?M49.Thiscompoundhasbeen repor&d to attenuate the amnesic effects of two drugs with conflict~~~~~ which facilitates the effects oi GABA, and the GABAA receptor bicuctdline. The efficacy Cattenuatetheamnesia caused by chlordiazepoxide was antagonized by bicuculline. Fu&enmne, this compound was to ameliorate the amnesic 82 ef&z? of cidoheximide, scopolamine, hemicholinium-3, basal -rain lesions, ekctroconvulsive shock, picrotoxin and ethanol (see Ref. 7). However, the specific behavioral and neuronal mechanisms involved in the drug’s effects and the dinical potential of such a ‘universal attenuator’ remain undear. Based on such preclinical findings, an impressive number of indications has been proposed for
tations of the predictive validity of preclinical data. The failure to determine the validity of the different behavioral paradigms (see Box) and of animal models used for the characterization of ncotropics may represent a major basis-for incorrect predictions of clinical efficacy.
“\ ,..JrCH,C~C”
,-, CnACH, o-selegiline
the nootropics (see Ref. 10). However, results flwn umhuiied dfnkal MaIs (which inch&d patients suffering from senik demenHa”*12, akohol organic disorder’) or age-associated cognitive dysfunctions”) indicate profound limi-
Cognition
enhan-nt
ChOhWdllld
Via
IMC-
Unlike the research on the nootropics, the search for cognition enhancers that operate via cholinergic mechanisms has been fostered by a rationale that was derived
zxhbasic
from
newopathdogical
psychobiological reDiverse experimental appro&hes have consistendy
suggested that the cognitive dysfunctions associated with normal aging or with degener&ve disorders are based on disruption of cholinergic functions’? The cholinergic hypothesis has, however, not been fully supp@ed by basic reseti on the functions of theforebrainchdinergicsystemor by clinical data, and thus has come under attackn*16. l!oosting this dialectic process, Fib&r” recently umduded that programs aimed at develop@ chobxgic pharmacothempies for the cognitivedeficitsinsefdledementiaare based ‘more on faith than on established f&s’. Indeed, there is littk knowMge of the specific cognitive fimctions that are dependent on forebrain choliergic
TiPS - December 1991/Vol. 121 I
The diffkulties of successfully predictingthe clinical etXcacy
putative cognition enhancers appear k~ely due to me uncertainty about the validity of animal models and
of
behavioral methods (see Ref. 1 and main text). since the mnal mechanisms that mediate cognitive functions are Pooay u&Mood, and as there is no consensus about the spe&ic pslrrhobgicsl components of tha w or dementiaassociated impairmbs In cognitive abilities, a straight validation of pmdinical test systems forcognition enharwm is not possible. Howwer, similar to WiW2 WabtiOn of animal modeis of depmssive disorders, a set of general validation criteria can be applied to determine the rig nificsnce of the various animal models and behavioral tests.
forexampkautomaticvemus
Coasbnct t&f&y An animal mode! may show good constructvalidity if it reflectsetioiogicalor other theoretical
;iptiuns about the symptums to be mudelled. Some of the most relevant exsmpks rue animak with cholinergic hypafwtb that has been induced surgicallyor phkmacologkally. Ibe modeis have been considered to possess
goadamstructvalidityastheyarebasedonthehypothmis itive impsirments in aging snd dementia are s that the resuh of“gp: fun&ma1 or structural dedine in forebrain cholinergicsystems. Howevar, the construct validity of thsss madebhasbsencriticiaedandauatificdu.Forexarnnk. aredueto~c&dtadeofmuscsrinica&khohm teceptors,itisthelossofpmsyn+icchohne@neumns thatmaympresentamajorneumnalcorreiateofdementia. Asecc&exampleistheextenttowhichthebahsviorsl unpdrnrmtr produced by exdtoWc acid-induced bass1 forebrain lesions are due to choiinergiccell loss? GOdC!OMUCtValidityd~snimrlmodeliS~
but tn&ficient w a b&s for generating widence of cognitive arhmamcnt. For example,attributing predictive validity(seebeiow)toatestsuchasantagonismofthe effectsof -tally induced choiinergic hy@unction, is@stifW(67diffwentdmgshsvebeenreporkdto attenUe behavioral effectsof acopolamint’).Thewnstruct
systems, and current animal models of the behavioral consequences of cholinergic hypofunction are of limited validity. However, since changes in cholinergic activity correlate with dementia, and since the behavioral pharmacology of cholinergic drugs has consisteutly suggested that the cholinergic system is prominently involved in cognitive processes, the hypothesis that cognition enhancement is mediated via stimulation of choiinergic activity remains attractive’s. Meanwhile, the discrepancy between preclinical efficacy of chohnomimetics and discouraging results from clinical trials indicates that caution is necessary. Table II lists putative cognition enhancers thought to act via cholinomimetic mechanisms, and indicates whether tire/ have &en
tested in clinical settings. The data from these trials suggest that muscarinic acetylchohne receptor agonists do not produce beneficial cognitive effects, and whilecholinesterase inhibitors did have effects,
indeioxazine they were considered ‘of heuristic rather than clinical significance”6 (see also Refs 7 and 19). Inappropriate pharmacokinetic properties and inadequate clinical pmtocob have been suggested to contribute to this lack of effica$‘. Also, muscarinic agonists and cholinester- inhibitors maydisrupt the patterning of cholinergic trans-
mission; however, it has been hypothesized that patterning rather than the absohrte amount of acetylcholine, is critical for signal pmcessit$‘. TheAxe, the potential of pmcholinergic mecha&ms for mediating cognition enhancement cannot be judged on the basis of the effects of conventional cholinomimetics. This may be relevant to the action of nicotine, which improves attentional processing in demented patienhll, since the extent to which this effect is due to release of acetylchohne is unknown
Modulatin the activity of presynaptic cho! inergic neurons and thereby preseming physiological signal transmission has been considered an advantageous
EPS - December 2991IVol. 121
459
kvant to the primary dysfunctions in human amnesia and
rmt a ta+ for drug-induced cognition enhancement. Determination of the face validity of a behavioral parap is a chaUen@g exercise, requiring sophisticated and A. --l-uJRP “1 A ,I...M~l t.“UI~9cl113 _U”_..k ,115 ~..“..&cL. *ysrun LL_.‘ VSIIY..wSU a test procedure. Contradictorymsults were Wned with ckmidine in aged nonhuman primates that
m &ted in tasks for recent spatipl mem~ry~~, which + aEke from a concephralbut not a hxhnical point of ew - indicating the potential gravity of this problem. W
t&&y An imxeasing number of putative cog&on enhancers are being tested in healthy humans and in @ous dinical conditions. Paradoxically, the drugs that em identified by, for exampie, passive avoidance tasksbut iMtoehowe~~indinialbiJs,hhrs~rrsultedina aaring re-evahzation of the (face and construct) validity !dab w using thii pamdigm. The value of fzlinical * is aiso shown by the discqmq in the effects of mddine (eae above). As the p&i&on that ‘admneqic @sta might &niiarly be helpful for pat-c@ with lsMner% diws~e’~ has not been confirm#~“, greater IMitymaybea&&utedtothoeeellperimental~ ~txsveal donidine-induced enhancement of 0
0
cl
matton of a single aspea of validity (face or conntct)ofananimalmodelorabehavioraitestpmcedun to ensure that the results will have ‘. However, a combination of both face x z
were examin& in scopolamine-treated primates !!!!!% 8-r I -r, .ld.“Yl -_ b..L. I” n&h- -, v -u,?? -UII “I uM=. “Y&Y=, ~~~~emplbycd an animal model of Hmited but
defined construct validity, and a behavioral paradii that permits variation of the cognitive task demands. physostigmine attenuated the effects of sqolamine but not the similar effects of eithez agins extended retention in&v*, __ ._ -_-_A uw --A Ucnl~Icc ~-_-._.a --_L1__._ --- L.~_ “I AlA.-A^YIDUHUVII. M S”mvcIs1R -- .~
sensitive to inte&ence during retmt& intuvals~‘the results by Rutmiak et al.” oredict that in-induced amnesia-will hot be atten&ed by physost@ine, and that scopolamine does not model thii situation. This type of research, which aims at identifying the specific cognitive defects impkmmted by an animalmodel,and de&mining the exact psychok+) nature of a drug effect, will significantly increax the predictive validity of preclinical data.
References 1 Sarter,M., Hagan,J.J. and Dud&e&o, P. pSychophnrm~c&gy (in pcsa) 2 Wittner, P. (Ml6) f’#yd+armaco&y 83,1-16 3 Hagan.].J.andMmTi&RC.M.(1968) the Aging Nwvow Systm Ufmdbwlr of 20) kmsen, I.. L, Ivemen,S. D. and Snyder,S. H., eds), pp: 237-323,PlsnumPress 4 Fib@, Ii. C (1991)Tmdr NeuraJn’14,~223 . 5 Robtdna,7. W. d rl. (l9B9)NCU&M 2s.337-352 6 Morris, R. G. ht. (1%) in Nrmmbidqy of LeaendMemory (Lynch, G., ffiugh, J. L and Wein-, N. M.. eds), PP. 119-124,Guildbrd Ress 7 Heiav,G. A. (1964)Mrd. Rcs.Rev.4, Sx-!i58 8 Olton, D. S. and w, A. L (MB) Neumbiol.Aging9, 46M74 9 Iaquierda,1.(19&) Ten& P/wnwol. !ki. 7,47U77 10 A.rnsten,A. F. T. and Goktmm-Rakic,P. S. (1985)S&ace 7.30, 1273-1276 11 Bartus,R T. and Dean. R L (MS) Ncumbiol.A& 9, Iop-lll 12 ~“;;R.$,an, M. J. and Downs,D. A. (1966)Dnig Dcu. 13 M&r, ‘E.et al. (1969)Arch.Neural.46,376-378 14 Scklegd,J. cl al. (lm Cfin.Neuropbarmafm. 12.174-126 .c .1 .1 I *._ R. n., IF, c 3. I.,t c1-l-I c~nu, .m.. J.1 iid 12 ~..-I_,_ mupnlu. iv. .a m. ,.,. 1_--, Ivmm, S. D. (1991)Behm.BruinRcs.43,1-6
properties of most of these cominterfere with potential beneficial effects on cognitive processes, some benzodiazepine re,cH*lcn,l,cwJ+li* :: ceptor ligands appear to combine properties typical of inverse agonists (in terms of inhibition of CABAergic transmission and facilitation of behavioral functions) with the abstince of proconvulsive -- a”rWgenlc __..:_-__:_ _..-_-_C___^_ or prupWun I^_ (VTCYell with anticonvulsive effects; see listed in Table II may involve MDL26479).As the inverse agonisttranssynaptic mechanisms. Inlike effects of these compounds verse agonists at the benzoappear most obvious on behavioral diazepine receptor are proposed facilitation, they have therefore to allow a rigorous test of this bern termed benzodiazepine restrategy. Specifically, it has been ceptor-selective inverse agonists%. hypothesized that these comThe biochemical and behavioral pounds stimulate acetylcholine reproperties of the @-carWine lease in the forebrain via negative ZK93426 have previously beenreallastcrlc modulation of GABAviewed*‘. Table III summarizes ergic transmission at chollnergic the data on a novel prototype cell bodic~*‘~. While the procompound that appearsto stimuconvulsive and p4blyanxiogenic
alternative to traditional cholinomimetld”. Some of the acetylcholine-releasing compounds
pounds
late acetylcholine anabolism as a result of benzodiazepine receptor-mediated inhibition of GABAergic transmission, the triazole MDL26479 (Ref. 25). Both ZK93426 and MDL26W9 increase forebrain &olinergic transmission (Reb 25, 26; j. A. Miller rt ul., unpublished) and
acecliiine the effects of experimentally induced disruption of cholinergic transmission (Ref. 21; M. garter cf al., unpublished). However, the extent to which drug-induced behavioral facilitatIon depends on the increase in choline&c activity is unknown. attenuate
TiPS - December 1991/Vol. 121
460 TABLE III. Phwt’naWqif3f
pmpertias of MM26479 Et&l
Test Diw
Longng
of [W)fbmazenil binding
potentialion in h@pocampal
spaw defay6d aflemabon piwmance in rals(d&Jys:2-32swxlds) .Sco@amina (0.03 ~0.1 mg kg-$ndwed fmpa#manl h spatiaf delayed afferfwion we
EDw = 0.22+0.05 mg kg-’ hp. in viva, mou5ecwfex coltex: 133% ilwease hippccamW:~ChfWP anfago&m(fntefmsofB,;ncwoflhe lmabnen~~~ hfippocapuscA1: 224% fncreaae hippocMprschu:216%inaesse dWWBgyius:WJChMge noeffecfs(l-3Wngkg-‘:Ef&,,~ fbmazw: 5.83fng kg-‘) nOellee6(upW?gWJkg-‘) noeffectsiuplo3omgkg-‘) increased ampfifuda of basaf population SW(lMqru) no effecfs (0.10-6.25 mg kg-‘) anlagonism
From Ref. 25: J. A. Miller efaf., ~npubilShed:M. Sable?etaf.. Unpbffshed.
cognition-enhancing As the properties of ZK93426 have been confirmed in intact human volunteers*‘, transs);napticaily induced stimulation of cholinergic activity appears to represent a promising neuronal mechanism for druginduced cognition enhancement. Drugs acting via non-cholinergic Table N indicates the diverse non-cholinergic mechanisms that have been considered targets for the induction of cognition enhancement. Although most of the compounds listed in this Table have not been studied extensively, beneficial effects on mental abilities m humans have been consistently predicted but rarely confirmed 5; human trials (see, for example, Reb 28 and 29; but them are promising effects in aged or demented humans reported for sabeluzoldO and selegiline3rX). Thus, the discrepancy between the optimistic predictions based on animal behavioral pharmacology and the dissatisfying findings in humans (a picture that also emerged from the discussion of nootropics and cholinomimetics) again su ests that conclusions fromp z* nncal research strategies and methods are invalid (see Box). =I
@
0
Resealh on cognition enhancers has focused on the demonstration of a wide range of drug effects in diverse behavioral tests and animal models, probably reflecting
the fact that ‘standard’ compounds are not available. Furthermore, the lack of knowledge about ‘pharmacologically accessible’ neuronal mechanisms that mediate complex mental abilities, and about the SpWifk psychological abilities that are potentially subject to pharmacological enhancement, has contributed to an uncritical use of behavioral tests with limited or unresolved validity (in terms of examining relevant cognitive func-
tions). Consequently, a relatively high number of false-positive cognition enhancers has been detected. Some criteria and procedures that may be useful for determining the validity of such tests and models have been proposed (see Ref. 7 and Box). In spite of these problems (which are possibly typical for a juvenile science), promising new compounds have emerged as putative cognition enhancers. several studies in human
milacemide volunteers and in patients with age-associated cognitive dysfunctions or dementia have confirmed that drug-induced cognition enhancement is a therapeutic possibility. Confirmation and psychological specificathm of the cognition-enhancing prqrties of promising drugs would provide the necessary tools for basic and applied research on the neuronal mechanisms of cognitiwpm03ses. Acknowl+stsenb The Box is based on a paper (Psychopkanacofogy, in press) that is co-authored by Jim Hagan (SmithKline Rae&am, Harlow) and Paul Dudchenko (Ohio State
TiPS - December 1991 Md. 121
University). I am indebted to them. I am grateful to J. Bruno and P. Dudchenko for discussions on earlier drafts of this manuscript. Research was supported by the US Public Health Service grants NIA AGlOl73-01 and MH 46869. OlAl, The Ohio Department of Aging (ADR-l-90), The American Federation for Aging Research, and the Sandoz Foundation for Gerontological Research. Referawes 1 Crwk, 2, &rtus, R., knir, S. and cmhon,
S., ads (1966) Treatmrnf De-
Strategtes r&pmrt DisrHe,Ma?kpwley~.
fir
Akhtimer’s
2 Mow. H., Davis, R., Schwarz, R. D. and Ganuu, E. (19&l) Med. Res. Rcu. 3, 353-w 3 Pumdt, R. D. (198s) Tr&s Phanoacol. 56-i.10.3-6 4 Ruhhins, T. W. (19&a) Nufurc 336, 207-2txi -_. -_ 5 CiurBea, C. U. (19S2) Drug Dm. Rn. 2, 441-446 h Nlcholaun, C. D. (1990) Rythophanna. cofogy101, 147-159
7 Sarter, hf., Ha~im, 1.1. and Dudchanko, P. Psycho@arwacolo~y(in press) 8 Ha~an, J.J.md Monk It.G.M.(196s) In PayckoPbanaacofog of thr Agiag Newour System fifa r&o k o( Psychopharmacology, Vol. 20) (Iwrmen, I.. L., Iveraen, S. D. and Snyder, S. H., eda), pp. 237-323, Plenum Press
9 Nabeahima.
T.,
Toyama,
K. and
Kameyama, 7: (1990) Phatwcrol. Biochew. B&PI). 36. -236 10 Ba~na, C. A., I’omam, N., Cmok, T. and Gemhun, 5. (1986) in Treatment
Ddopmrnt Stratqie for Ahhrimrr’s Dfsease Oook, T., Sartus, R.. Ferris, S. and Gemhan, S., edr), pp. 55%X Mark Powkv Assoc. 11 Claus, ). J. ;t of. (1991) Nrrmfogy 41, 570-574 12 Ctuwdon, J. H., Corkin, S., Huff, F. J. and Rosen, T. ). (19B6) Ncarobiol. Aging
461
15 Bartus, R. T., Dean, R. L., Pontacorvo, M. J. and Rkker, C. (1986) in Memory Dysfuncfious:Iufcgmtion of Animal and Hawn Rewarch from CIinical and Preclinical PrrspCrrmes(Cltut~, D., Camzu, E. and Corkin, S., ads), pp. 332-35& NY Academy of Sciences 15 HaBan, J. J. in Anti-dementia AgentsRcscarck and Prospects for Tbcrapy (Nichulscm,C. D.. ed.). Academic Press (in press) 17 Fib@, H. C. (1991) Tends Nc~rraxr. 14,
2%223 18 Sartar, M., Bruno, J. P. and Dudchenko, P. (1991) Twtkr Neuroscf. 11,484 19 Becker, R. E. and Ciacubini, E. (19B5) Drug Dro. Rcs. 12,163.195 20 Bartus, R. T. (1990) 1. Am. Crriatr. 5oc. 3BbSB695 21 Sarter, M., Bruno, J. P. and Dudchenku, P. (19%) Psychophanoacofogy 101, l-17 22 Sahakian, B., Jones, C., Levy, R.. Gray, 1. and Warburtun, D. (19B9) Br. 1. ky-
chialry 154, 797-SOO 23 Salter, M., Schneider. H. H. and Stephens, D. N. (1988) Trruds Neamsci. 11.11-17 24 S&r,
54. (1990) Eur. 1. Pbom~acol.177,
155-162 25 Milkr, J. A. and ChmieIewski. P. A. (1990) 5or. Nrrroaci. Abstr. lb, 91.11 26 Bruno, J. P., Moora. H., Dudchenku, P. and Sarter, M. in Tbc Trcatmrnt ~1 Dzncntias: A Nrw Cramtion of Progress
(Mayer, E. M., Cm,
F. T. and Simg
kins, J. W., eds), pknum Press(in press) 27 Duka, T., Stephena, D. N., Krause, W. and Domw, R. (1907) Psychophawaacology93,421Xi7 28 Markstein. R. (1969) Eur. Nrurof. 29 ~Suppl.), u-4 29 F;rndpg, Tz (1990) New Eql.
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<.
H. C., Tritsmans, I., C., Amery. W. K. and Janssen, P. A. J. (198R) Psychophamacology94,52-57 31 Tariot, P. N. rt al. (19S7) Psychophmacology9L4S9-495 32 Man@, A. cl al. (1991) Eur. Ncuml. 31, 1MlW Idrikowski.
BDwllsc (s)-2,S.dimethyl-1,3-dioxa.Burrpimt4.5&cana(Z)-2-butenedioate CBBu6733r2-methyl-or-eaocryph Cl979! o-l2#5~tet&ydr&IZyI.~ pyrfdlne arhuaaI~DmethyIoxime mcmuhydmchbrI& DM93Mt N-(2,&dImethyi.phenyB.2-(zuau-l-pyrruRdinyl)-acatamide I)llpr)6e 33bfs(4pyrindinytmethI;l)-lphenyIindoIin-2-cme B2S2&(2).23.dihydru-5,6-dimethaxycthmy2-(Il-(phmymwUlyl~4-pi~~~inyl]methyl]-Hi-inden-1.une Fl
Hoe17513,S-dbnethyi4phenyl-S&7,& tetrahydm-pyrazow3*4.w5)diaaapim.1H,4H-5,7-diie Hpo19. (*I-9-amino-1,234. tetmhydmacridin-l-d-maieate 1CS%593&(k-tmpanyI)-lH.;adole-3~ carboxyIicacid eater JOl7tN (+)_N-cyc~yl-methyl-Nmethyl-1,4.diphenyI-l-yi-but+en-l-
ylrmine hydmchbridc MClZt?It I-@-benr/lpfwnoxy)-Nmethylbutylaminehydmcbbride MM161798S-(3-Suompbenyl~.2Adbnethyl.3%1,2#ria&-3.tbi~ NIWII: 9-amino-2.3~$,7#-heaahydm. llf.cy&panta~b]quinoRne munuhydrate hydmehknide
(45)-decan-1,3-dimte-Iwdmhmmide
SDZRNA7Is: (-)N-ethyl-N-methyl-O’-(l”dimethylaminu)-ethyi)-pbmyi-carbamata hydrogan(rtirate SDR2lambf (-)12-mathyl-spiru-(0 dimtuIan-4,4’l-l’-methyI-piperidinhydvfenmaIata
SMlWSW-~illO-8-tlUlU-l~,4. g$z$-g~;~~ (4.phenylbutyt)pho@inylloxyWc=o. newl-2-wdim
-fJ2ai-rleaaharbr
7,~27b I3 Bamaa, C., Miller, C, Gunther, V. and Ileiuhhacker, W. (1987) Pro& NearoPs~ychoPharwacol. Biol. Psychiatry 11,
v-9-M: vaI-Rn-vaI-Glu-AIa-vaI-Asp.pru. Met
729-737 14 Reiabeq, C. et rl. (1982) Dn18 Duu. RES.
~~~~~hyl~
2,475-480
YMl467& Nq[($~2-
carbulhw-3-c-