Novel (R)-2-amino-5-fluorotetralins: dopaminergic antagonists and inverse agonists.
A series of secondary and tertiary N-alkyl derivatives of (R)-2-amino-5-fluorotetralin have been prepared. The affinities of the compounds for [3H]raclopride-labeled cloned human dopamine (DA) D2 and D3 receptors as well as [3H]-8-OH-DPAT-labeled rat hippocampal 5-HT1A receptors were determined. In order to selectively determine affinities for the high-affinity agonist binding site at DA D2 receptors, the agonist [3H]quinpirole was used. The intrinsic activities of the compounds at DA D2 and D3 receptors were evaluated in a [35S]GTP gamma S binding assay. The novel compounds were characterized as dopaminergic antagonists or inverse agonists. The antagonist (R)-2-(butylpropylamino)-5-fluorotetralin (16) bound with high affinity (Ki = 4.4 nM) to the DA D3 receptor and was the most D3-selective compound (10-fold). (R)-2-[[4-(8-Aza-7, 9-dioxospiro[4.5]decan-8-yl)butyl]propylamino]-5-fluorote tralin (18) bound with very high affinity to both DA D3 and 5-HT1A receptors (Ki = 0.2 nM) and was also characterized as a dopaminergic antagonist. (R)-2-(Benzylpropylamino)-5-fluorotetralin (10) behaved as an inverse agonist at both DA D2 and D3 receptors. It decreased the basal [35S]GTP gamma S binding and potently inhibited the DA-stimulated [35S]GTP gamma S binding. It is apparent that the intrinsic activity of a 2-aminotetralin derivative may be modified by varying the N-alkyl substituents.
Department of Organic Pharmaceutical Chemistry, Uppsala Biomedical Center, Uppsala University, Sweden.
A
A
Malmberg
B B
BB
Höök
A M
AM
Johansson
U
U
Hacksell
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000378:metabolism; D000818:Animals; D018491:Dopamine Agonists / Q000737:chemistry* / Q000378:metabolism; D018492:Dopamine Antagonists / Q000737:chemistry* / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D008297:Male; D020891:Raclopride; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000378:metabolism; D044263:Receptors, Serotonin, 5-HT1; D012457:Salicylamides / Q000378:metabolism; D013764:Tetrahydronaphthalenes / Q000737:chemistry* / Q000378:metabolism
D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012457:Salicylamides; D013764:Tetrahydronaphthalenes; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D020891:Raclopride; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin