Characterization of dopamine receptor subtypes by comparative structure-activity relationships: dopaminomimetic activities and solid state conformation of monohydroxy-1,2,3,4,4a,5,10,10a-octahydrobenz[g]quinolines and its implications for a rotamer-based dopamine receptor model.
A series of phenolic (cis)- and (trans)-1,2,3,4,4a,5,10,10a-octahydrobenz[g]quinolines were investigated in the D1 and D2 dopamine (DA) models, DA-sensitive adenylate cyclase and electrically evoked acetylcholine release, respectively, and were compared with the effects of the corresponding aminotetralins. A similar structure-activity pattern was found at both DA receptor subtypes. The change from the bicyclic to the tricyclic DA analogs resulted in a loss of activity of all beta-rotameric 8-hydroxy derivatives, suggesting the presence of a steric barrier. Derivatives of the alpha-rotameric 6-hydroxy trans series, in contrast to their inactive cis analogs, showed stimulatory effects that increased from N-methyl to N-n-propyl substitution, indicating an interaction with an N-alkyl binding site. The inactivity of the corresponding N-n-butyl derivative ("N-butyl phenomenon") suggests that the N-alkyl substituents of this series point toward a "small N-alkyl binding site," which can be differentiated from a "large N-alkyl binding site." An X-ray of the active (-)-enantiomer of (trans)-6-hydroxy-N-n-propyloctahydrobenz[g]quinoline-(R)-mandelat e revealed a 4aR, 10aR absolute configuration, corresponding to that of (-)-5-hydroxy-2-(N,N-di-n-propylamino)tetralin. The hydrogen bonding interactions of the axial N+-H proton and the hydroxy group to mandelate anions in the crystal provide a model for a possible drug-receptor interaction. Molecular modeling served to localize the steric barrier and the boundaries of the small N-alkyl binding site, which together form an "extended steric barrier." The results led to the proposal of a refined version of a rotamer-based general DA receptor model, which is supplemented by criteria for the orientation of DA agonists. Its application is demonstrated with apomorphine and ergoline.
Seiler
M P
MP
Preclinical Research, Sandoz Ltd., Basel, Switzerland.
Markstein
R
R
Walkinshaw
M D
MD
Boelsterli
J J
JJ
D000109:Acetylcholine / Q000378:metabolism; D000262:Adenylyl Cyclases / Q000032:analysis; D000818:Animals; D002417:Cattle; D015259:Dopamine Agents / Q000494:pharmacology*; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D011954:Receptors, Dopamine / Q000032:analysis / Q000187:drug effects*; D013329:Structure-Activity Relationship
D015259:Dopamine Agents; D011804:Quinolines; D011954:Receptors, Dopamine; D000262:Adenylyl Cyclases; D000109:Acetylcholine