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

Bioorg Med Chem Lett. 2007 Mar 15;17(6):1570-4. doi: 10.1016/j.bmcl.2006.12.106. Epub 2007 Jan 8.


In continuation of our work on N-(piperidin-4-yl)-naphthamides, the effect of substituted benzyl groups on D(2L), D(4.2), and 5-HT(2A) receptor affinity was evaluated. In the 1-naphthamide series most compounds were highly selective for D(4.2) over D(2L) and 5-HT(2A) receptors. Halogen and methyl substitution in position 3 or 4 of the benzyl group increased D(4.2) affinity. In the 2-naphthamide series a similar high D(4.2) over D(2L) selectivity was retained while 5-HT(2A) affinity was increased. 3-Methoxy, 3-methyl, and 4-methyl substituents were favorable for D(4.2) affinity while halogens reduced affinity. 2-Naphthamides with a 3-bromo- or a 3-methyl group were mixed D(4.2)/5-HT(2A) ligands similar to their unsubstituted parent compound. All compounds from both series with significant affinity for D(4.2) and 5-HT(2A) receptors were antagonists.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Benzyl Compounds / chemical synthesis*
  • Benzyl Compounds / pharmacology*
  • Humans
  • Indicators and Reagents
  • Ligands
  • Naphthalenes / chemical synthesis*
  • Piperidines / chemical synthesis*
  • Rats
  • Receptor, Serotonin, 5-HT2A / drug effects*
  • Receptors, Dopamine D2 / drug effects*
  • Receptors, Dopamine D4 / drug effects*
  • Structure-Activity Relationship


  • Benzyl Compounds
  • Indicators and Reagents
  • Ligands
  • Naphthalenes
  • Piperidines
  • Receptor, Serotonin, 5-HT2A
  • Receptors, Dopamine D2
  • Receptors, Dopamine D4