Design and Synthesis of Bitopic 2-Phenylcyclopropylmethylamine (PCPMA) Derivatives as Selective Dopamine D3 Receptor Ligands

Abstract

2-Phenylcyclopropylmethylamine (PCPMA) analogues have been reported as selective serotonin 2C agonists. On the basis of the same scaffold, we designed and synthesized a series of bitopic derivatives as dopamine D3R ligands. A number of these new compounds show a high binding affinity for D3R with excellent selectivity. Compound (1R,2R)-22e and its enantiomer (1S,2S)-22e show a comparable binding affinity for the D3R, but the former is a potent D3R agonist, while the latter acts as an antagonist. Molecular docking studies revealed different binding poses of the PCPMA moiety within the orthosteric binding pocket of the D3R, which might explain the different functional profiles of the enantiomers. Compound (1R,2R)-30q shows a high binding affinity for the D3R (K i = 2.2 nM) along with good selectivity, as well as good bioavailability and brain penetration properties in mice. These results reveal that the PCPMA scaffold may serve as a privileged scaffold for the design of aminergic GPCR ligands. PCPMA part was reduced to an ethoxy group in compounds 16b, 17c, and 17d, which resulted in slight increases in binding affinities, as can be seen by comparing 17d versus 17b, 17c versus 17a, and 16b versus 16a. When the ethoxy substituent on the benzene ring was further truncated to a methoxy group, binding affinities were further increased, as can be seen from compounds 16c, 17e, and 17f, with the last showing a K i value of 44.0 nM at D3R. The N-ethyl group was changed to a propyl (17g), an isopropyl (17h), or a cyclopropylmethyl group (17i), but none of these compounds showed an increased affinity for D3R compared to the N-ethyl compound 17f. The fluorine atom on the left-hand benzene ring was changed to a Cl atom in compounds 17j, 17k, and 17l, with various N substitutions, and these compounds showed Scheme 4. Synthesis of compounds (1R,2R)-22e and (1S,2S)-22e a a Reagents and conditions: (a) chiral prep-HPLC separation; (b) 4 M HCl in dioxane, rt, overnight, 98%; (c) propionaldehyde, NaBH 4 , NEt 3 , dioxane, rt, 10 min, 34−63%; (d) 20c, NaHB(AcO) 3 , THF, rt, overnight, 32−33%.K i values were calculated from mean pK i values (mean pK i ± SEM values from at least three individual experiments are provided in Table S1). b All compounds were tested as HCl salts. c NT, not tested.

Dopamine Receptor Subtypes, Physiology and Pharmacology: New Ligands and Concepts in Schizophrenia

“…Several groups have generated a variety of synthetic ligands concurring to build similar molecular models including dynamic aspects of DR receptor activation over time. In recombinant systems at least, we witness some amazing activity switches between agonist and “antagonist” properties across different series that require further dynamic considerations ( Tan et al., 2020 ). Destabilization of D3 inactive state(s) and flexibility of the ligands are among the elements that the most recent model available is proposing ( Ferraro et al., 2020 ).…”

Discovery of Homobivalent Bitopic Ligands of the Cannabinoid CB2 Receptor**

“…Bitopicl igandst hat targett he orthosteric site and the receptor vestibule improve selectivity, [11,12] off-rates and signalingb ias, [4,13,14] maintaining bioavailability and brain penetration properties in mice. [15] Othert ype of comparable ligands are designed to simultaneously bind two orthosteric sites of a( homo/hetero) GPCR dimer. [16] These type of ligands have been recently reviewed.…”

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

“…Tan et al have exploited the basic 2-phenylcyclopropylmethylamine (PCPMA) scaffold ( 8, 9 ), whose analogues are known 5-HT 2C R agonists ( Cheng et al, 2015 ; Cheng et al, 2016a ; Cheng et al, 2016b ; Zhang et al, 2017 ), to design new bitopic compounds ( Tan et al, 2020 ) ( Supplementary Table S3 ). Here we discuss only a subset of these compounds.…”

“…For these compounds, only N-alkyl substituted variants have been prepared and the effects of several PPs have been investigated. When examining the racemic compounds, the compound containing 4-pyridylphenyl SP and dichlorophenyl PP ( 20 ) has more than 1000-fold selectivity towards the other DRs, with milder but still significant selectivity in the range of 17 , 18, and 19 ( Tan et al, 2020 ) ( Table 1 ).…”

“…Investigating pure enantiomeric forms of compounds 17–20 ( Supplementary Table S3 ) Tan et al showed that the (R,R) enantiomers ( 17b-20b ) have a better affinity for D 3 R than (S,S) ( 17a-20a ), with the exception of compound 17 , which had an identical affinity for both of the enantiomers ( 17a, 17b ) ( Tan et al, 2020 ). The (R,R) isomers ( 17b-20b ) showed weaker affinity (3–20-fold) towards 5-HT 2C R than their (S,S) counterparts ( 17a-20a ).…”