Affinity for Dopamine D₂, D₃, and D₄Receptors of 2-Aminotetralins. Relevance of D₂Agonist Binding for Determination of Receptor Subtype Selectivity

Abstract

A series of 2-aminotetralins, substituted with a methoxy or a hydroxy group on the 5- or 7-position, and with varying N-alkyl or N-arylalkyl substituents, were prepared and evaluated in binding assays for human dopamine (DA) D2, D3, and D4 receptors. Some members of this series were prepared in former studies, but were never tested in vitro with single receptor subtypes, and these were examined again. None of the tested 2-aminotetralins showed high affinity for the dopamine D4 receptor. However, a number of the 2-aminotetralins showed high affinity for both the D2 and the D3 DA receptors, as exemplified by compounds 11-15 and 21-26, while some had a reasonable selectivity for the DA D3 receptors. The affinities of the 2-aminotetralins for the D21, receptor depended on the type of radioligand (agonist or antagonist) used. The agonist affinity data, obtained by using the agonist ligand [3H]N-0437, are thought to be more relevant for calculating DA receptor subtype selectivity.

Synthesis of some urea and thiourea derivatives of 3-phenyl/ethyl-2-thioxo-2,3-dihydrothiazolo[4,5-d]pyrimidine and their antagonistic effects on haloperidol-induced catalepsy and oxidative stress in mice

“…In addition, the electron attractive groups decrease the binding affinity, while electron donors like -OCH 3 increase the affinity for the binding at the dopamine D 2 receptor in comparison with the unsubstituted analogues [43,44]. Also, methoxy group is said to be linked with binding affinity of the drug molecules at dopamine D 2 and D 3 receptor sites [43].…”

Dopamine D3 receptor agonists as pharmacological tools

“…In illustration of the SBP hypothesized butyl linker for dopamine D 3 receptor specificity is implemented. represented for rigid 5-OH-DPAT and 7-OH-DPAT, respectively (Van Vliet et al, 1996). 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 .…”

“…Aminotetralines can also be taken as core structure for other aminergic receptors as they have the 2-(hetero)arylethanamine moiety in common (Dijkstra et al, 2002). For dopaminergic receptors an aromatic hydroxy function in 5-or 7-position enhances affinity as well as selectivity, while methoxy groups at this position as hydrogen acceptors cannot maintain affinity (Elsner et al, 2005;Van Vliet et al, 1996). Concerning the substitution pattern on the basic amine, n-propyl moieties are affinity increasing, whereas in disubstituted analogues larger variations with potential binding properties to the secondary binding pocket (SBP) are tolerated (Cannon, 1983;Dijkstra et al, 2002;Seiler et al, 1986;Van Vliet et al, 1996).…”

“…For dopaminergic receptors an aromatic hydroxy function in 5-or 7-position enhances affinity as well as selectivity, while methoxy groups at this position as hydrogen acceptors cannot maintain affinity (Elsner et al, 2005;Van Vliet et al, 1996). Concerning the substitution pattern on the basic amine, n-propyl moieties are affinity increasing, whereas in disubstituted analogues larger variations with potential binding properties to the secondary binding pocket (SBP) are tolerated (Cannon, 1983;Dijkstra et al, 2002;Seiler et al, 1986;Van Vliet et al, 1996). Nevertheless this "simple" agonist class is clearly marked by a low bioavailability due to the fast phase II metabolization on the phenolic moiety which takes also place for the inactivation of the endogenous ligand (Dijkstra et al, 2002).…”

Selective Agonists for Dopamine/Neurotensin Receptor Heterodimers

“…To confirm that the allosteric effect across the receptor-receptor interface is exerted by specific agonist binding, further control experiments were performed. In earlier studies, we described two mutations in the extracellular loop of NTS 1 (W129A and W134A), which show a complete loss in agonist binding of [ 3 H]NT (8)(9)(10)(11)(12)(13) , but which exhibit retention of antagonist binding of [ 3 H]SR4869. [8] We produced transiently co-expressing cell lines of D 3 and NTS 1 W129A or NTS 1 W134A.…”