Aminopyrimidines with High Affinity for Both Serotonin and Dopamine Receptors

Abstract

A series of [4-[2(4-arylpiperazin-1-yl)alkyl]cyclohexyl]pyrimidin-2-ylamine s was prepared and found to have receptor binding affinity for D2 and D3 dopamine (DA) receptors and serotonin 5-HT1A receptors. The structural contributions to D2/D3 and 5-HT1A receptor binding of the aminopyrimidine, cycloalkyl, and phenylpiperazine portions of the molecule were examined. From these studies compounds 14, 39, 42, 43, having potent affinity for both DA D2 and 5-HT1A receptors, were evaluated for intrinsic activity at these receptors, in vitro and in vivo. Compound 14 (PD 158771) had a profile indicative of partial agonist activity at both D2 and 5-HT1A receptors causing partially decreased synthesis of the neurotransmitters DA and 5-HT and their metabolites. This compound has a profile in behavioral tests that is predictive of antipsychotic activity, suggesting that mixed partial agonists such as 14 may have utility as antipsychotic agents with increased efficacy and decreased side effects.

Preparation of two D2 partial agonists in C‐14 and stable isotope labeled forms

“…HPLC analysis using method A showed 80% radiochemical purity with a single 20% radiolabeled impurity. This impurity co-eluted on HPLC with (S)-benzyl [2][3][4][5][6][7][8][9][10][11][12][13][14]…”

“…1 The approval of aripiprazole (Abilify W ), a D2 partial agonist with activities at multiple 5-HT receptors, prompted active research and development of various D2 partial agonists, on the basis of the hypothesis that D2 partial agonists with an appropriate level of intrinsic activity at D2 receptors can regulate dopamine activity to normal levels in neurons in either hyperdopaminergic or hypodopaminergic states, while minimally disturbing other normal dopaminergic pathways, leading to antipsychotic efficacy and a potentially superior side effects profile. [2][3][4][5][6][7] Compounds 1 and 2 ( Figure 1) were identified as partial D2 receptor agonists and were required in labeled form to further probe their biological activity. 8…”

Dopamine D3agonists

“…PD 158771 (trans-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl]-cyclohexyl}-pyrimidin-2yl-amine) was identified and has been characterised as a dopamine autoreceptor agonist and a partial dopamine D 2 and D 3 agonist [36,37]. It is also an antagonist at dopamine D 4 and an agonist at 5-HT 1A receptors.…”

Syntheses of Some New N‐Linked Pyrimidine‐2‐amines with Pyrazinopyrimidines, Thienopyrimidines, and Benzazoles via Reactions of Various Nucleophiles with Cyanamides

“…. Its derivatives possess diverse biological activities, for example, cardioprotective , antipsychotic , antitubercular , antimalarial , and antitumor . Mostly, the formation of heterocyclic 2‐aminopyrimidine system was pursued via reactions of nucleophilic substituted guanidine with diverse bi‐electrophiles, such as β ‐dicarbonyl, β ‐ketoester, enone, and enaminone derivatives .…”