PT  - JOURNAL ARTICLE
AU  - M P Seiler
AU  - R Markstein
AU  - M D Walkinshaw
AU  - J J Boelsterli
TI  - 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.
DP  - 1989 May 01
TA  - Molecular Pharmacology
PG  - 643--651
VI  - 35
IP  - 5
4099  - http://molpharm.aspetjournals.org/content/35/5/643.short
4100  - http://molpharm.aspetjournals.org/content/35/5/643.full
SO  - Mol Pharmacol1989 May 01; 35
AB  - 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.