Aromatic Substituent on the Pyrazole

February 23, 2024

• Title:       

  Aromatic Substituent on the Pyrazole 

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  4-Heterocyclylpiperidines as selective high-affinity ligands at the human dopamine D4 receptor

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  Table 3

• Associated context:

  The lipophilic group at the other end of the molecule  is also important for binding (Table 3). When the  4-chlorophenyl ring attached to the pyrazole is replaced  with a simple methyl group (12), binding to hD4 is  reduced by a factor of 50 compared to the analogous  compound (9). Again, the chlorine atom on this benzene  ring is not required for binding, with removal giving a  compound (13) with the same affinity for hD4 as that  of compound 9. However, there is a doubling of hD2 affinity on removal of this chlorine atom, so selectivity  is correspondingly reduced. The attachment of the  benzene ring directly to the pyrazole is important, with  the homologous benzylpyrazole 14 losing 15-fold in hD4  binding, despite the fact that the distance (in number  of atoms) between the two benzene rings is the same  as for compound 10. Since it had been established that  the best substituent on the basic nitrogen is phenethyl,(16). The three pyridyl isomers (17-19) have similar  profiles, with a small reduction in binding to hD4  receptors when compared to the benzene ring, along  with a smaller reduction in hD2 affinity. None of these  changes show benefit over the (4-chlorophenyl)pyrazole  present in the lead.