Analogues of Arylamide Phenylpiperazine Ligands To Investigate the Factors Influencing D3 Dopamine Receptor Bitropic Binding and Receptor Subtype Selectivity

ACS Chemical Neuroscience
Hamed S HayatshahiRobert R Luedtke

Abstract

We have previously reported on the ability of arylamide phenylpiperazines to bind selectively to the D3 versus the D2 dopamine receptor subtype. For these studies, we used LS-3-134 as the prototypic arylamide phenylpiperazine ligand because it binds with high affinity at D3 dopamine receptor (0.17 nM) and exhibits >150-fold D3 vs D2 receptor binding selectivity. Our goal was to investigate how the composition and size of the nonaromatic ring structure at the piperazine position of substituted phenylpiperazine analogues might influence binding affinity at the human D2 and D3 dopamine receptors. Two factors were identified as being important for determining the binding affinity of bitropic arylamide phenylpiperazines at the dopamine D3 receptor subtype. One factor was the strength of the salt bridge between the highly conserved residue Asp3.32 with the protonated nitrogen of the nonaromatic ring at the piperazine position. The second factor was the configuration of the unbound ligand in an aqueous solution. These two factors were found to be related to the logarithm of the affinities using a simple correlation model, which could be useful when designing high affinity subtype selective bitropic ligands. While this model is based u...Continue Reading

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Citations

Oct 22, 2019·Bioorganic & Medicinal Chemistry Letters·Nagaraju BashettiKiran Kumar Solingapuram Sai
May 15, 2021·Journal of Chemical Information and Modeling·Hamed S HayatshahiJin Liu
Jun 3, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Boeun LeeRobert R Luedtke
Aug 14, 2020·ACS Chemical Neuroscience·Hamed S Hayatshahi, Jin Liu

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