van der Weide, Jan

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   University of GroningenDetermination of the pharmacological profile of the dopamine agonist N-0437van der Weide, JanIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:1988Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):van der Weide, J. (1988). Determination of the pharmacological profile of the dopamine agonist N-0437.s.n.CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 21-06-2022SummaryIn  t h i s  t hes i s  va r i ous  pha rmaco log i ca l  i nves t i ga t i ons  pe r fo rmed  w i thN-0437 are descr ibed.Chapter  I  ' is  an in t roduct ion to the exper imenta l  chapters of  th isthes i s .  I t  dea l s  w i t h  t he  ro le  o f  dopamine  i n  t he  b ra in ,  t he  d i seasesin  wh i ch  dopamine  i s  ' i nvo l ved ,  c l ass  i f i ca t i ons  o f  t he  dopaminereceptor  and ' i t  prov ides a rev iew of  the most  se lect ive dopamineagon i s t s  and  an tagon i s t s .Chapter  I I  conta ins a shor t  desc-r ip t ion of  the test  models wh' ich havebeen used ' in  the exper imenta l  chapters I I I  t / rn  IX.  In  the ' la t terchapters these test  models are therefore only br ie f ly  ment ioned.  Th ' ischap te r  a l so  con ta ins  t he  mos t  recen t  v i ews  on  the ' i nvo l vemen t  o f  D - land D-2 receptors in the pharmacological test systems. Moreover thesyn thes i s  o f  N -0437  i s  desc r i bed .Chapter  I I I  is  a s tudy,  conta in ing a compar ison between N-0437 and twoanalogues.  N-0434 and N-0734.  The test  models used are main ly  in  v ivotes t  mode ls  f o r  po tency  and  se lec t i v i t y .  Behav iou ra l  as  we l l  asb iochemica l  s tud ies  a re  desc r i bed .  The  mos t  ' i n te res t ' i ng  resu l t s  o ft h i s  chap te r  a re  t he  h igh  o ra l  ac t i v ' i t y  and  the  l ong  du ra t i on  o fact ion of  N-0437.Chap te r  IV  dea l s  w i t h  t he  i n  v i t r o  ac t i v i t y  o f  t r i t i um- labe l l ed  N -0437.  3H-t r t -O+:U appeared a ' lso in  v i t ro to be a very potent  dopamineagon i s t ,  wh ' i ch  was  se lec t i ve  f o r  D -?  recep to rs .  Dopamine  agon i s t s  andan tagon i s t s  w i t h  D -2  ac t ' i v i t y  a re  po ten t  d i sp lace rs ,  wh i l s t  d rugsbe long ing  to  va r i ous  o the r  pha r rnaco log i ca l  c l asses  appea r  t o  be  ve ryD O O r  O n e S .Chap te r  V  i s  an  i n  v i t r o  s tudy  on  the  e f f ec t s  o f  chemica l  l es ions  andthe in f luence of  metal  ions and GTP on the b inding of  3H- l t -O+:Z to D-Zreceptors.  From the les ion exper iments i t  became c lear  that  3t t - l t -O+:Zpreferent ia l ly  b inds to postsynapt ic  dopamine receptors,  GTP and Na+are  ab le  t o  dec rease  the  spec i f i c  b ind ing  o f  3H- | ! -O+ :Z  wh i l e  Hg* *c o m p l e t e l y  n u l l i f i e d  t h e  b i n d i n g .Chapter  VI  is  a s tudy per formed in col  laborat ion wi th otherl abo ra to r i es .  I t  dea l s  abou t  t he  po tency  and  se lec t i v i t y  o f  r acemic  N -0437 for  dopamine receptors,  N-0437 was tested for  a possib lediscr iminat ion between pre-  and postsynapt ic  dopamine receptors inv i vo  as  we l l  as  i n  v i t r o ,  and  i n  add i t i on  f o r  poss ib le  se ro tone rg i cact iv i ty  in  v jvo.  I t  appeared that  racemic N-0437 does not  d iscr imi-nate between the pre-  and postsynapt ic  receptors and in addi t jonshowed  no  se ro tone rg i c  ac t ' i v i t y  i n  v i vo .  I n  t h i s  s tudy  we  a l so  t es tedthe in  v i t ro af f in i ty  of  racemic N-0437 for  var ious non-dopaminergicreceptors.  I t  appeared that  N-0437 was about  280 t imes more se ' lect ivefor  D-? receptors than for  o2*adrenergic  receptors.  For  other  k ' inds ofreceptors the se. lect iv i ty  rat io  was many more t imes b i99er .Chapter  VI I  descr ibes an in  v i t ro autoradiograph' ic  s tudy wi th rH-N-0437.  This work was per formed in the research laboratory of  Sandoz inBase l .  Because  o f  t he  l ow  non -spec i f i c  b ind ing  o f  3H-N-0437 ,  t h i scompound appears to be an excel lent  radio l  igand to v isua' l ize the D-2recep to rs  i n  t he  b ra in .  The  pha rmaco log i ca l  p ro f i  l e  and  sa tu rab i  l i t yobta ined wi th autoradiography were in  very good agreement  wi th the inv i t r o  rad io l i gand  b ind ing  s tud ies  desc r i bed  i n  chap te r  IV .Chap te r  V I I I  Th i s  chap te r  dea ' l s  w i t h  ce r ta in  mo1ecu la r  p rope r t i es  o fthe DA receptor .  I t  has been descr ibed jn l i terature that  dopamineantagonists  are ab ' le  to protect  dopamine receptors against  N-ethoxycarbony' l -2-ethoxy-1,2-d ' ihydroquinoi ine (EEDQ) induced receptorinact ivat ion.  I t  has a lso been repor ted that  dopamine agonists  andan tagon ' i s t s  b ind  to  d i f f e ren t  b ind ' i ng  s i t es .  Because  o f  t he  se lec t i v j -ty  of  N-0437,  th is  compound was tested for  i ts  poss ' ib ' le  protect ingcapaci ty .  In  contrast  to  dopamine antagonists ,  N-0437 was not  able toprotect  the dopamine D-2 receptor  against  EEDQ induced inact ivat ion,Chapter  IX In the la t ter  s tages of  th is  research pro ject  racem' ic  N-0437 was resolved into the (+)  and ( - )  enant iomers.  These opt ica lant ipodes were examined in test  models for  pre-  and postsynapt icdopaminergic  act ' iv i ty .  I t  appeared that  the (+)  enant iomer a is  vsryselect ive presynapt ic  agonist  and a postsynapt ic  antagonist ,  whi le  the(- )  enant iomer is  a fu l l  agon' is t  and labels both pre-  and postsynapt icreceptors.These propert ies are of  importance for  therapeut icapp l i ca t i on .From the above studies i t  can be concluded that  N-0437 is  a verypotent  and select ive dopamine D-2 receptor  agonist .  Racemic N-0437 iscapab' le  of  s t imulat ' ing both pre-  and postsynapt ic  receptors.  The (+)enant iomel i  s  a par t ia l  dopamine agon' is t .  whereas the ( - )  enant iomeri s  a  f u11  agon i s t .  Because  o f  i t s  po tency  and  se lec t i v ' i t y ,  h i gh  o ra lact iv i ty  and long durat ion of  act ' ion,  th is  compound is  a verypromis ing candidate for  therapeut ic  use.  The (+)  enant iomer could havean appl icat ion for  the t reatment  of  schizophrenia as i t  s t imulates invery low concentrat ions presynapt ic  dopamine receptors.  The ( - )enant iomer is ,  because of  i ts  potency on postsynapt ic  receptors,  is  ave ry  p rom is  i ng  d rug  fo r  Pa rk inson ' s  d i sease .

Determination of the pharmacological profile of the dopamine agonist N-0437

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Determination of the pharmacological profile of the dopamine agonist N-0437

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