Benzyl Phenylsemicarbazides: A Chemistry-Driven Approach Leading to G Protein-Biased Dopamine D4 Receptor Agonists with High Subtype Selectivity
Many subtype-selective dopamine receptor ligands developed for the D2-D4 family incorporate a 1-arylpiperazine-derived primary recognition motif, which is connected to a lipophilic moiety occupying an extended binding pocket (EBP) of the receptor via an aliphatic linker of variable lengths. The evaluation of a novel group of dopamine receptor ligands now showed that highly subtype-selective ligands [up to Ki(D4.4) = 0.25 nM, D2L/D4.4 = 320, D3/D4.4 = 710 for APH199 (17)] can be obtained by choosing a relatively large and conformationally flexible 1-benzyl-1-phenylsemicarbazide substructure to fill the EBP. The novel chemotype APH199 (17) was found to act as a full agonist at the D4 receptor showing significant bias toward G protein activation over β-arrestin recruitment in comparison to quinpirole.
Pirzer, Anna S.,Lasch, Roman,Friedrich, Heike,Hübner, Harald,Gmeiner, Peter,Heinrich, Markus R.
p. 9658 - 9679
(2019/11/13)
Alkylaminobenzothiazole and -benzoxazole derivatives
PCT No. PCT/EP97/02505 Sec. 371 Date Nov. 9, 1998 Sec. 102(e) Date Nov. 9, 1998 PCT Filed May 2, 1997 PCT Pub. No. WO97/43271 PCT Pub. Date Nov. 20, 1997The present invention concerns the compounds of formula the N-oxide forms, the pharmaceutically accept