Tetrahydroisoquinolines as dopaminergic ligands: 1-Butyl-7-chloro-6-hydroxy-tetrahydroisoquinoline, a new compound with antidepressant-like activity in mice.
Three series of 1-substituted-7-chloro-6-hydroxy-tetrahydroisoquinolines (1-butyl-, 1-phenyl- and 1-benzyl derivatives) were prepared to explore the influence of each of these groups at the 1-position on the affinity for dopamine receptors. All the compounds displayed affinity for D(1)-like and/or D(2)-like dopamine receptors in striatal membranes, and were unable to inhibit [(3)H]-dopamine uptake in striatal synaptosomes. Different structure requirements have been observed for adequate D(1) or D(2) affinities. This paper details the synthesis, structural elucidation, dopaminergic binding assays, structure-activity relationships (SAR) of these three series of isoquinolines. Moreover, 1-butyl-7-chloro-6-hydroxy-tetrahydroisoquinoline (1e) with the highest affinity towards D(2)-like receptors (K(i) value of 66nM) and the highest selectivity (49-fold D(2) vs D(1)) by in vitro binding experiments was then evaluated in behavioral assays (spontaneous activity and forced swimming test) in mice. Compound 1e increased locomotor activity in a large dose range (0.04-25mg/kg). Furthermore, this lead compound produced reduction in immobility time in the forced swimming test at a dose (0.01mg/kg) that did not modify locomotor activity. The haloperidol (0.03mg/kg), a D(2) receptor preferred antagonist, blocked the antidepressant-like effect of compound 1e.
Berenguer
Inmaculada
I
Departamento de Farmacología, Facultad de Farmacia, Universidad de Valencia, 46100 Burjassot, Valencia, Spain.
El Aouad
Noureddine
N
Andujar
Sebastián
S
Romero
Vanessa
V
Suvire
Fernando
F
Freret
Thomas
T
Bermejo
Almudena
A
Ivorra
María Dolores
MD
Enriz
Ricardo D
RD
Boulouard
Michel
M
Cabedo
Nuria
N
Cortes
Diego
D
D000818:Animals; D000928:Antidepressive Agents / Q000737:chemistry* / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine; D006912:Hydroxyquinolines / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D008297:Male; D051379:Mice; D008958:Models, Molecular; D009043:Motor Activity / Q000187:drug effects; D011485:Protein Binding; D051381:Rats; D011954:Receptors, Dopamine / Q000737:chemistry / Q000378:metabolism*; D017447:Receptors, Dopamine D1 / Q000737:chemistry / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000737:chemistry* / Q000494:pharmacology*
C544094:1-butyl-7-chloro-6-hydroxytetrahydroquinoline; D000928:Antidepressive Agents; D006912:Hydroxyquinolines; D008024:Ligands; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D044005:Tetrahydroisoquinolines; D004298:Dopamine