Synthesis and preliminary pharmacological evaluation of 5-hydroxy- and 5,6-dihydroxy-1,2,3,7,12,12a-hexahydrobenzo[5,6]cyclohepta[1,2,3-ij]isoquinoline derivatives as dopamine receptor ligands.
A series of 5-hydroxy- and 5,6-dihydroxy-1,2,3,7,12,12a-hexahydrobenzo[5,6]cyclohepta[1,2,3-ij]isoquinoline derivatives (5a--e and 6a--e) were synthesized as conformationally rigid analogues of 1-benzyltetrahydroisoquinoline and evaluated for their affinity at D(1) and D(2) dopamine receptors. All compounds showed lower D(1) and D(2) affinities than dopamine. The 5-hydroxy-1-methyl-2,3,12,12a-hexahydrobenzo[5,6]cyclohepta[1,2,3-ij]isoquinoline 5a and the 5,6-dihydroxy analogue 6a showed D(2) agonist activity. This was proved by their effects on prolactin release from primary cultures of rat anterior pituitary cells. Molecular modeling studies showed that the geometric parameters (namely the distances from meta and para hydroxyl oxygens to the nitrogen and the height of nitrogen from the hydroxylated phenyl ring plane) of the dopaminergic pharmacophore embedded in our compounds have lower values in comparison with those observed in D(1) and D(2) selective ligands.
Cingolani
G M
GM
Dipartimento di Scienze Chimiche, Università di Camerino, Via S. Agostino 1, 62032 Camerino (MC), Italy.
Di Stefano
A
A
Napolitani
F
F
Mosciatti
B
B
Giorgioni
G
G
Cinone
N
N
Brunetti
L
L
Luisi
G
G
Michelotto
B
B
Orlando
G
G
Costa
B
B
Lucacchini
A
A
Martini
C
C
Claudi
F
F
D000818:Animals; D002478:Cells, Cultured; D003508:Cycloheptanes / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D018491:Dopamine Agonists / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D007546:Isoquinolines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009010:Monte Carlo Method; D010903:Pituitary Gland, Anterior / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011388:Prolactin / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011954:Receptors, Dopamine / Q000187:drug effects / Q000378:metabolism*; D013329:Structure-Activity Relationship
C435806:5,6-dihydroxy-1,2,3,7,12,12a-hexahydrobenzo(5,6)cyclohepta(1,2,3-ij)isoquinoline; D003508:Cycloheptanes; D018491:Dopamine Agonists; D007546:Isoquinolines; D008024:Ligands; D011954:Receptors, Dopamine; D011388:Prolactin