Novel (R)-2-amino-5-fluorotetralins: dopaminergic antagonists and inverse agonists.
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Malmberg A, Hook BB, Johansson AM, Hacksell U
Novel (R)-2-amino-5-fluorotetralins: dopaminergic antagonists and inverse agonists.
J Med Chem. 1996 Oct 25;39(22):4421-9.
- PubMed ID
- 8893836 [ View in PubMed]
- Abstract
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.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Dopamine Dopamine D2 receptor Ki (nM) 1.89 N/A N/A Details Dopamine Dopamine D2 receptor Ki (nM) 572 N/A N/A Details Dopamine Dopamine D3 receptor Ki (nM) 13.2 N/A N/A Details Haloperidol Dopamine D2 receptor Ki (nM) 0.16 N/A N/A Details Haloperidol Dopamine D2 receptor Ki (nM) 0.66 N/A N/A Details Haloperidol Dopamine D3 receptor Ki (nM) 2.74 N/A N/A Details