Synthesis and in vitro binding studies of substituted piperidine naphthamides. Part II: Influence of the substitution on the benzyl moiety on the affinity for D2L, D4.2, and 5-HT2A receptors

Computer-Aided Design and Biological Evaluation of Diazaspirocyclic D4R Antagonists

“…The application of spirocycles to drug discovery efforts has increased in recent years as a means to increase compound three-dimensionality, modulate DMPK properties, incorporate additional sp 3 centers, and generate novel intellectual property. − One of the central findings of the present study was the discovery of 2,7-diazaspiro[3.5]­nonane as an applicable core motif for selective D 4 R antagonists. While we initially identified the highly potent antagonist VU6052469 , which exhibited a high degree of structural similarity to a previously reported selective D 4 R antagonist, it notably lacked selectivity (Figure B,D,E). We postulated that this lack of selectivity arose from the difference in length between these two compounds, with the naphthalene and 4-chlorobenzyl moieties of the Carato compound potentially leading to poorer steric interactions within the TM2/3 pocket of D 2 R than the dimethylphenyl and 3,4-difluorobenzyl moieties of VU6052469 (Figure E).…”

“…(C) D 4 R hit-rate for experimentally validated molecules. (D) 2D structures of Carato et al: compound 22 ( 71 ) and VU6052469 . (E) Overlay of docked poses of Carato et al: compound 22 ( 71 ) and VU6052469 within D 4 R.…”

Update 1 of: Recent Progress in Development of Dopamine Receptor Subtype-Selective Agents: Potential Therapeutics for Neurological and Psychiatric Disorders

“…A series of novel 1-and 2-naphthamides showed varied selectivity for D 4 and 5-HT 2A over D 2 receptors. 410,411 In general, N-(1-arylalkylpiperidin-4-yl) carboxamides had higher affinity than corresponding N-(4-arylalkylaminopiperidin-1yl)carboxamide analogs (Figure 42). A benzyl moiety in position 1 of the piperidine ring in 2-naphthamide-containing compounds appears to be the best choice for interaction with D 4 and 5-HT 2A receptors; for example, representative compound 499 had K i values of 11 and 44 nM for D 4 and 5-HT 2A receptors, respectively.…”

“…The most potent D 4 ligand of the 1-naphthamide series is compound 500, containing a phenylpropyl moiety and possessing moderate D 4 (K i = 63 nM) and lower 5-HT 2A affinity (K i = 50 nM). 410 In addition, the effect of substituted benzyl groups on D 2 , D 4 , and 5-HT 2A receptor affinity was evaluated. A halogen, methoxy, or methyl substituent in position 3 or 4 of the benzyl group enhanced D 4 affinity.…”

“…Increasing the linker length between the phenyl ring and the basic nitrogen led to decreased affinity for both receptors. The most potent D 4 ligand of the 1-naphthamide series is compound 500 , containing a phenylpropyl moiety and possessing moderate D 4 ( K i = 63 nM) and lower 5-HT 2A affinity ( K i = 50 nM) …”