- Email: [email protected]
Non-classical neuroleptic-like properties of partial dopamine agonists
183
D.M. Ccward (*), K. Dixon, A. Enz, J.-M. Moeglen, S. Umyler, T. h%ite Sa_rdozResearch Institute Ewne Ltd., P.0. Eox, m-3001 Ekrne, Switzerland Existinganti-s&izophrtmicagents oweboththeirdesirable (antipsychotic) andundesirable (&pyramidal side-effects)actionstotheirabilityto blockcentraldopaminerecepto~. 0nepotentialwayofachievingthe former effect in the absence ofthelatteristodeveloppartialdopmineagonkts. Ideally, such agents should exhibit high affinity for IF2 receptor and, at the sametime, alimitedstimulatoxyactionatthis site. Theiractionsare ofrelevancetothetreatmfzntofschizophreniasincetheyexhibit Wualistic~~pmperties, actingasdopamine antagonistsinmepresenceof excessive~dopmineqic activity or, conversely,agcmistsinthepresenceof hypodaparmnersicactivity. Thus, they should be effective against positive synptmsiftheseresultfmrnexcessived opamimqic activity and, possibly, deficit state. At the against negative sy@cms ifthesereflectadqxmine sametime,thereshouldbelittleornodistu&mce ofextrapyramidalmtor function. SD2
208-911 and SD2 208-912 are amim-eqolinesexhibitingpartialdopamine agonistic activity in the rat, whereby SD2 208-911 is clearly more agonistic dqamine deficit situation than is SDZ 208-912. Amngst othem, they xngly inhibit dopamineagonist-inducedstemtypieswithakinduciq significantcatalepsy, reduceconditionf3davoidancerespo~mre selectivelythan haloperidol,suppress pmlactin secretion and, in 6hydrmrydapamine-lesionedrats,causevaryingdegreesofcontrdlaterdl circlingbehaviour. Confirmationof their partial agonistic activity at the central level is afforded by SD2 208-911'spartial reversal of gamnabU@mlactOne (GBL)-inducedincrease of striatal L-DoPAsynthesis, andSDZ 208-912's partial reversal of apcxmrphinetsinhibitoryeffect on GBL activity. Inhealthymalevolunteers, singleoraldosesofSD!Z 208-912 producea neuroleptic-like picture, includingsedationardpmlactinelevation. In ~~,limitedf~~frcan4~treatmentinschiz~cinpatients indicatesalackofaartettystoniasorParkinsonsyndrcane,andeitherno change or a clear suppressionof prolactin release. Tllesefindingssuggest that the "dopaminergicstatus~tofschizophrenicsubjectsmi~tindeeadiffer frmthatofnormal irdividualsandclearlywarmntthe furtherclinical testing of this type of agent.
D.M. Ccward (*), K. Dixon, A. Enz, J.-M. Moeglen, S. Umyler, T. h%ite Sa_rdozResearch Institute Ewne Ltd., P.0. Eox, m-3001 Ekrne, Switzerland Existinganti-s&izophrtmicagents oweboththeirdesirable (antipsychotic) andundesirable (&pyramidal side-effects)actionstotheirabilityto blockcentraldopaminerecepto~. 0nepotentialwayofachievingthe former effect in the absence ofthelatteristodeveloppartialdopmineagonkts. Ideally, such agents should exhibit high affinity for IF2 receptor and, at the sametime, alimitedstimulatoxyactionatthis site. Theiractionsare ofrelevancetothetreatmfzntofschizophreniasincetheyexhibit Wualistic~~pmperties, actingasdopamine antagonistsinmepresenceof excessive~dopmineqic activity or, conversely,agcmistsinthepresenceof hypodaparmnersicactivity. Thus, they should be effective against positive synptmsiftheseresultfmrnexcessived opamimqic activity and, possibly, deficit state. At the against negative sy@cms ifthesereflectadqxmine sametime,thereshouldbelittleornodistu&mce ofextrapyramidalmtor function. SD2
208-911 and SD2 208-912 are amim-eqolinesexhibitingpartialdopamine agonistic activity in the rat, whereby SD2 208-911 is clearly more agonistic dqamine deficit situation than is SDZ 208-912. Amngst othem, they xngly inhibit dopamineagonist-inducedstemtypieswithakinduciq significantcatalepsy, reduceconditionf3davoidancerespo~mre selectivelythan haloperidol,suppress pmlactin secretion and, in 6hydrmrydapamine-lesionedrats,causevaryingdegreesofcontrdlaterdl circlingbehaviour. Confirmationof their partial agonistic activity at the central level is afforded by SD2 208-911'spartial reversal of gamnabU@mlactOne (GBL)-inducedincrease of striatal L-DoPAsynthesis, andSDZ 208-912's partial reversal of apcxmrphinetsinhibitoryeffect on GBL activity. Inhealthymalevolunteers, singleoraldosesofSD!Z 208-912 producea neuroleptic-like picture, includingsedationardpmlactinelevation. In ~~,limitedf~~frcan4~treatmentinschiz~cinpatients indicatesalackofaartettystoniasorParkinsonsyndrcane,andeitherno change or a clear suppressionof prolactin release. Tllesefindingssuggest that the "dopaminergicstatus~tofschizophrenicsubjectsmi~tindeeadiffer frmthatofnormal irdividualsandclearlywarmntthe furtherclinical testing of this type of agent.