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

Taking advantage of our in-house experimental data on dopamine D3 receptor modulators, we have successfully established highly significant CoMFA and CoMSIA models (qcv2=0.82/0.76). These models were carefully investigated to assure their stability and predictivity (rpred2=0.65/0.61) 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.

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