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

Bioorg Med Chem Lett. 2007 Mar 15;17(6):1565-9. doi: 10.1016/j.bmcl.2006.12.096. Epub 2007 Jan 8.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / chemistry*
  • Amides / metabolism*
  • Animals
  • Binding, Competitive / drug effects
  • Guanosine 5'-O-(3-Thiotriphosphate) / metabolism
  • Humans
  • Indicators and Reagents
  • Naphthalenes / chemical synthesis*
  • Nitrogen / chemistry*
  • Piperidines / chemical synthesis*
  • Rats
  • Receptor, Serotonin, 5-HT2A / drug effects*
  • Receptors, Dopamine D2 / drug effects*
  • Receptors, Dopamine D4 / drug effects*
  • Structure-Activity Relationship

Substances

  • Amides
  • Indicators and Reagents
  • Naphthalenes
  • Piperidines
  • Receptor, Serotonin, 5-HT2A
  • Receptors, Dopamine D2
  • Receptors, Dopamine D4
  • Guanosine 5'-O-(3-Thiotriphosphate)
  • Nitrogen