Synthesis and in vitro binding studies of substituted piperidine naphthamides. Part I: Influence of the substitution on the basic nitrogen and the position of the amide on the affinity for D2L, D4.2, and 5-HT2A receptors.
A series of 1- and 2-naphthamides has been prepared and tested for in vitro binding to D(2L), D(4.2), and 5-HT(2A) receptors. Different compounds display selectivity for D(4.2) and 5-HT(2A) receptors versus D(2L) receptors. N-(1-Arylalkyl-piperidin-4-yl) carboxamides have higher affinities than the corresponding N-(4-arylalkylamino-piperidin-1-yl) carboxamide analogues. A benzyl moiety in position 1 of the piperidine in the 2-naphthamide series (2) appears to be the best choice for a favorable interaction with D(4.2) and 5-HT(2A) receptors. Increasing the linker length between the phenyl ring and the basic nitrogen led to a decreased affinity for these receptors. In the 1-naphthamide series, the most potent D(4.2) ligand (7) possesses a phenylpropyl moiety while its affinity for 5-HT(2A) receptors is strongly reduced. All compounds with significant affinity for D(4.2) and 5-HT(2A) receptors were antagonists.
Carato
Pascal
P
Laboratoire de Chimie Thérapeutique, Faculté des Sciences Pharmaceutiques et Biologiques de Lille, 3 rue du Professeur Laguesse, BP 83, F-59006 Lille, France.
Graulich
Amaury
A
Jensen
Niels
N
Roth
Bryan L
BL
Liégeois
Jean-François
JF
D000577:Amides / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D007202:Indicators and Reagents; D009281:Naphthalenes / Q000138:chemical synthesis*; D009584:Nitrogen / Q000737:chemistry*; D010880:Piperidines / Q000138:chemical synthesis*; D051381:Rats; D044402:Receptor, Serotonin, 5-HT2A / Q000187:drug effects*; D017448:Receptors, Dopamine D2 / Q000187:drug effects*; D050638:Receptors, Dopamine D4 / Q000187:drug effects*; D013329:Structure-Activity Relationship
D000577:Amides; D007202:Indicators and Reagents; D009281:Naphthalenes; D010880:Piperidines; D044402:Receptor, Serotonin, 5-HT2A; D017448:Receptors, Dopamine D2; D050638:Receptors, Dopamine D4; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D009584:Nitrogen