5-Oxygenated N-alkyl- and N,N-Dialkyl-2-amino-1-methyltetralins. Effects of structure and stereochemistry on dopamine-D2-receptor affinity.
The ability of a series of stereochemically well-defined 5-oxygenated 2-aminotetralins, consisting of dopamine-receptor agonists and antagonists, to displace [3H]spiperone and [3H]N-propylnorapomorphine (NPA) from calf-caudate dopamine receptor sites has been evaluated in-vitro. In addition, the partition coefficients of the compounds were determined to measure their lipophilicity. The data were compared with previously obtained in-vivo biochemical data (dopa accumulation in reserpine pretreated or non-pretreated rats). Compounds with 2S-configuration and a C5-hydroxy substituent have the highest affinity for NPA-binding sites and such derivatives also have the highest potency in-vivo. The 2R-derivatives are less efficacious and their affinity for NPA- and spiperone binding sites is influenced by their lipophilicity. On the basis of these results, a model is proposed in which the antagonists form two, and the agonists form three, strong intermolecular bonds with the D2-receptor. According to this model, the agonists, but not the antagonists, are able to donate a hydrogen bond from the phenolic hydroxyl to the receptor.
Department of Medicinal Chemistry, State University of Groningen, The Netherlands.
C J
CJ
Grol
G
G
Nordvall
A M
AM
Johansson
U
U
Hacksell
D000818:Animals; D001058:Apomorphine / Q000031:analogs & derivatives / Q000378:metabolism; D001667:Binding, Competitive; D002417:Cattle; D003198:Computer Simulation; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D046508:Culture Techniques; D015259:Dopamine Agents / Q000378:metabolism; D010100:Oxygen / Q000494:pharmacology*; D011954:Receptors, Dopamine / Q000187:drug effects* / Q000378:metabolism; D017448:Receptors, Dopamine D2; D013134:Spiperone / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D014316:Tritium
D015259:Dopamine Agents; D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2; D013764:Tetrahydronaphthalenes; D014316:Tritium; D013134:Spiperone; C009074:N-n-propylnorapomorphine; D001058:Apomorphine; D010100:Oxygen