Thiazoloindans and thiazolobenzopyrans: a novel class of orally active central dopamine (partial) agonists.
The 2-aminothiazole moiety has proven its value in medicinal chemistry as a stable and lipophilic bioisosteric replacement of a phenol group. This approach has provided dopamine (DA) agonists with good oral availability. To further explore its use in the development of DA agonists, we have combined the 2-aminothiazole moiety with 2-aminoindans and 3-aminobenzopyrans, which are known templates for DA agonists. In this study we have synthesized 6-amino-3-(N,N-di-n-propylamino)-3,4-dihydro-2H-thiazolo[5, 4-f]-[1]benzopyran (12) and 6-amino-2-(N, N-di-n-propylamino)thiazolo[4,5-f]indan (20) and several analogues (13, 17, and 21). The affinity of the thiazolobenzopyrans and thiazoloindans for DA receptors was evaluated, which revealed compound 20 to have high affinity for DA D(3) receptors. In addition, the compounds were screened for their potential to inhibit lipid peroxidation, to determine their radical scavenging properties. Compounds 12, 20, and 21 were subjected to further pharmacological evaluation in a functional assay to determine intrinsic activity. Compound 20 was also studied with microdialysis (to determine effects on DA turnover in striatum) and in unilaterally 6-OH-DA lesioned rats (to determine their potential as DA agonists). These studies selected compound 20 (GMC 1111) as particularly interesting. Compound 20 caused a rotation activation in unilaterally 6-OH-DA lesioned rats and an increase in DA turnover in rat striatum. This dual agonist/antagonist action is best accounted for by its partial agonism at striatal DA D(2) receptors. Interestingly, 20 displayed long-lasting activity and excellent oral availability in 6-OH-DA lesioned rats, making this compound potentially useful for the treatment of Parkinson's disease.
van Vliet
L A
LA
Department of Pharmacology, Faculty of Medicine, University of Maastricht, Postbus 616, NL-6200 MD Maastricht, The Netherlands. l.a.van.vliet@farm.rug.nl
Rodenhuis
N
N
Wikström
H
H
Pugsley
T A
TA
Serpa
K A
KA
Meltzer
L T
LT
Heffner
T G
TG
Wise
L D
LD
Lajiness
M E
ME
Huff
R M
RM
Svensson
K
K
Haenen
G R
GR
Bast
A
A
D000284:Administration, Oral; D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D002455:Cell Division / Q000187:drug effects; D003342:Corpus Striatum / Q000378:metabolism; D006224:Cricetinae; D018491:Dopamine Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D016166:Free Radical Scavengers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007189:Indans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects; D017551:Microdialysis; D011714:Pyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011954:Receptors, Dopamine / Q000378:metabolism; D013239:Stereotyped Behavior / Q000187:drug effects; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C414214:6-amino-2-(N, N-di-n-propylamino)thiazolo(4,5-f)indan; D018491:Dopamine Agonists; D016166:Free Radical Scavengers; D007189:Indans; D011714:Pyrans; D011954:Receptors, Dopamine; D013844:Thiazoles