Novel (R)-2-Amino-5-fluorotetralins:  Dopaminergic Antagonists and Inverse Agonists

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.

Direct dopamine D2‐receptor‐mediated modulation of arachidonic acid release in transfected CHO cells without the concomitant administration of a Ca2+‐mobilizing agent

“…Tentatively, this effect may be the result of so‐called inverse agonism (Kenakin, 1996). Recently, the assumption that D 2 receptors can indeed be the subject of inverse agonism has gained support also from studies by others (Giambalvo & Wagner, 1994; Hall & Strange, 1996a, b; Malmberg et al , 1996; Hall & Strange, 1997; Kozell & Neve, 1997). Notably, apart from the study by Giambalvo & Wagner (1994) using synaptoneurosomes prepared from rat neural tissue, all these examples of D 2 receptor‐mediated inverse agonism have been demonstrated in transfected systems characterized by an over‐expression of receptors.…”

Real‐time analysis of dopamine: antagonist interactions at recombinant human D2long receptor upon modulation of its activation state

“…Most of the dopamine antagonists have nonetheless been suggested to act as inverse agonists at the dopamine D 2 receptor (Hall & Strange, 1997; Strange, 1999), though these compounds, with the exception of (+)‐UH 232, could not be differentiated since they share a similar magnitude of inverse agonism. The weak amplitude of constitutive dopamine D 2 receptor activation (Malmberg et al ., 1996; Backlund Höök et al ., 1999; Choi et al ., 2000) as compared to other G protein‐coupled receptor systems (Daeffler & Landry, 2000) is perhaps one possible explanation for the apparent lack of differentiation between the intrinsic activity of these putative inverse agonists. We found clear differences in the activation profiles of both A371K and T372R D 2long receptor mutants by the partial agonists lisuride, (+)‐UH 232 and bromerguride.…”

“…Measuring forskolin‐stimulated cyclic AMP accumulation in transfected CHO‐K1 cells, Hall & Strange (1997) suggested that most antipsychotic drugs act as inverse agonists at both wild‐type D 2short and D 2long receptors. Also, these antagonists only weakly (<12%) inhibited basal [ 35 S]‐GTPγS binding to membranes expressing either the short or long isoform of the D 2 receptor (Malmberg et al ., 1996; Backlund Höök et al ., 1999; Choi et al ., 2000). One strategy to overcome this apparently weak amplitude of inverse agonist activity may be by introducing a facilitating mutation in the receptor sequence.…”

Dopamine D3 receptor agonists as pharmacological tools

“…Comparing binding affinities (Table 1) at different D 2 -like receptor subtypes, dopamine showed higher affinity at human D 3 over D 2 (K i hD 2 /K i hD 3 = 2-43), but highest affinity at D 4 . Data for binding affinities showed high variations with different cell systems and screening conditions, e.g., K i = 13-240 nM hD 3 (Dörfler et al, 2008;Gerlach et al, 2003;Malmberg et al, 1996;Sautel et al, 1995) and K i = 0.8-25 nM rD 3 (Chio et al, 1994;Sokoloff et al, 1990).…”