- 2-Phenylcyclopropylmethylamine Derivatives as Dopamine D2Receptor Partial Agonists: Design, Synthesis, and Biological Evaluation
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Partial agonist activity at the dopamine D2 receptor (D2R) is the primary pharmacological feature of the third-generation antipsychotics─aripiprazole, brexpiprazole, and cariprazine. However, all these drugs share a common phenyl-piperazine moiety as the primary pharmacophore. In this study, we designed and synthesized a series of novel compounds based on the 2-phenylcyclopropylmethylamine (PCPMA) scaffold and studied their pharmacological activity at the D2R. A number of potent D2R partial agonists were identified through binding affinity screening and functional activity profiling in both G protein and β-arrestin assays. The structure-functional activity relationship results showed that the spacer group is crucial for fine-tuning the intrinsic activity of these compounds. Compounds (+)-14j and (+)-14l showed good pharmacokinetic properties and an unexpected selectivity against the serotonin 2A (5-HT2A) receptor. Preliminary suppressive effects in a mouse hyperlocomotion model proved that these PCPMA-derived D2R partial agonists are effective as potential novel antipsychotics.
- Cheng, Jianjun,Fan, Luyu,Liu, Ruiquan,Tan, Liang,Wang, Huan,Wang, Sheng,Yan, Wenzhong,Yu, Jing
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p. 17239 - 17258
(2021/12/06)
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- Stereoselectivity and Generality of the Palladium-Catalysed Cyclopropanation of α,β-Unsaturated Carboxylic Acids Derivatized with Oppolzer's Sultam
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A series of α,β-unsaturated carboxylic acids derivatized with camphorsultam 1 a s a chiral auxiliary has been stereoselectively cyclopropanated. the selectivity of the reaction produces cyclopropanated products with the 1R,2R absolute configuration as indicated by the optical rotations as well as by an X-ray structure determineation.The temperature dependence of the reaction was studied with three substrates. the highest stereoselectivity was obtained at temperatures above 25 deg C.Branching at the α- or β-carbons disfavours complete conversion, and electron-withdrawing substituents at these positions seem to prevent the reaction.The auxiliary was removed by using titanium(IV) isopropoxide in benzyl alcohol followed by alkaline hydrolysis of the intermediate ester. the potent 5-HT1A receptor agonist (1R,2S)-2-(2-hydroxyphenyl)-N,N-dipropylcyclopropylamine 13 was synthesized by this method
- Vallaerda, Jerk,Appelberg, Ulf,Csoeregh, Ingeborg,Hacksell, Uli
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p. 461 - 470
(2007/10/02)
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