Design, synthesis, and evaluation of bitopic arylpiperazine-phthalimides as selective dopamine D₃ receptor agonists

Abstract

The dopamine D3 receptor (D3R) is a proven therapeutic target for the treatment of neurological and neuropsychiatric disorders.

Designing drugs and chemical probes with the dualsteric approach

“…In more cases, dualsteric modulators are designed by combining the orthosteric and allosteric ligand with a linker. 50,56,57,59,62,63,65,66,69,70,73,75,77–86,88,89,91,92,96,97,99,100,102–104,106–109,111,114–118,120–123,126,127,132,133,136,138,140,143,145,148–150,153,154,156,160,161,163,165,166,169,170,178–182,185,186,188,195,228 This is similar with the fragment-based drug discovery (FBDD). 229 The core fragments of drug binding is first identified and then the fragments are grown, merged, or linked into one complete molecule.…”

“…After a manual filtering, 133 research articles focusing on identifications of novel dualsteric modulators were found. Modulators targeting GPCR 50,53,56–137 or kinase 138–157 account for more than three quarters (Fig. 5).…”

“…GPCR itself has accommodated 62.4% targets of reports. 50,53,56–137 GPCR is a class of 7-transmembrane (7TM) proteins decorated on the cell membrane for transduction amplification of exterior signals into cells. 189 They are vital in many physiological processes and are therefore popular drug targets for a series of diseases like cancers and neurological disorders.…”

“…Dualsteric modulators, which bind to both orthosteric and allosteric sites, have been showing a good balance of potency and selectivity. 50,56,61–66,68,70,72,75,77–85,88,89,96–100,102,103,106,108,114,117,121–124,126,127,131,136,138,140,142–145,149,150,153,156,159–162,164–166,171–174,176,179–182,184–188,195–199 It could be found that the combined molecule would have a better selectivity than the orthosteric synthon while a better potency than the allosteric synthon. For example, Antony et al 136 designed a dualsteric modulator targeting muscarinic M 2 receptor (M 2 R).…”

The Impact of the Secondary Binding Pocket on the Pharmacology of Class A GPCRs

“…The approach was validated by the synthesis and experimental evaluation of the designed compounds. Classical docking and virtual screening approaches could be also utilized for the development of bitopic compounds ( Cao et al, 2018 ) and even to develop fluorescent GPCR probes ( Prokop et al, 2021 ). We highlight here a study that utilized structure guided design of GPCR polypharmacology ( Kampen et al, 2021 ).…”