Syntheses and molecular structures of 3-N, N-di-n-propylamino-2-chromanones as new analogues of dopamine.
A series of 3-N,N-di-n-propylamino-2-chromanones were synthesized as dopamine analogues. The lactone ring was introduced as a means to reduce their propensity to cross the blood-brain barrier and to avoid central side effects, rendering these compounds potentially useful for the treatment of glaucoma. Pharmacological activities were determined in vitro on rat striatum, by examining their capacity to displace the specific binding of the labeled dopaminergic ligand 3H sulpiride or 3H spiperone and 3H SCH 23390 for D2 and D1 sites, respectively. Compound 6a showed a weak dopaminergic activity on D2-receptors and no affinity for D1-receptors, which can be explained, at least in part, by a weak pKa and the presence of an internal hydrogen bonding. Furthermore, computer molecular modelling studies showed that the aromatic ring of 6a was negatively charged in contrast to the classical D2-agonists aminotetralin derivatives, hampering a possible interaction with a negatively charged area of the D2-receptor. These results, taken together, can account for the moderate dopaminergic activities exhibited by these lactone derivatives.
Benoit-Guyod
M
M
Groupe de Pharmacochimie Moléculaire, Université Joseph Fourier-Grenoble, France.
Nicolle
E
E
Namil
A
A
Coulombeau
C
C
Leclerc
G
G
D000818:Animals; D001812:Blood-Brain Barrier; D002867:Chromones / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D004298:Dopamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D005901:Glaucoma / Q000188:drug therapy; D006801:Humans; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D013329:Structure-Activity Relationship
D002867:Chromones; D017448:Receptors, Dopamine D2; D004298:Dopamine