Interactive SAR studies: rational discovery of super-potent and highly selective dopamine D3 receptor antagonists and partial agonists.
Starting from dopamine receptor ligand BP897, an interactive drug discovery process leading to heterocyclic bioisosteres is demonstrated. The four step strategy involved a careful optimization of geometric and electronic properties by systematic modification of the attachment points and heteroatoms, respectively. Efficacy tuning by modification of the phenyl substituents led to both D3 partial agonists and full antagonists. The benzothiophenes 3c (FAUC346) and 3d (FAUC365) revealed outstanding D3 affinity and subtype selectivity.
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D018491:Dopamine Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D008938:Mitosis / Q000187:drug effects; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D017448:Receptors, Dopamine D2 / Q000187:drug effects*; D050637:Receptors, Dopamine D3; D013329:Structure-Activity Relationship; D013552:Swine; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C493593:DRD3 protein, human; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; C467222:FAUC 346; C467223:FAUC 365; D008024:Ligands; D010879:Piperazines; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D013876:Thiophenes