CoMFA and CoMSIA investigations of dopamine D3 receptor ligands leading to the prediction, synthesis, and evaluation of rigidized FAUC 365 analogues Original Research Article

Taking advantage of our in-house experimental data on dopamine D3 receptor modulators, we have successfully established highly significant CoMFA and CoMSIA models (image). These models were carefully investigated to assure their stability and predictivity (image) and subsequently applied to guide experimental investigations on the synthesis and receptor binding of three conformationally restricted D3 ligands. Besides the high D3 affinity, the test compound 45, incorporating a trans-1,4-cyclohexylene partial structure, exhibited improved (∼3200-fold) selectivity over the D4 subtype.