1,3-Dioxolane-based ligands incorporating a lactam or imide moiety: structure-affinity/activity relationship at alpha1-adrenoceptor subtypes and at 5-HT1A receptors

Eur J Med Chem. 2010 Sep;45(9):3740-51. doi: 10.1016/j.ejmech.2010.05.023. Epub 2010 May 15.

Abstract

A series of 1,3-dioxolane-based compounds incorporating a lactam (2-4) or imide (5-7) moiety was synthesized and the pharmacological profile at alpha(1)-adrenoceptor subtypes and 5-HT(1A) receptor was assessed through binding and functional experiments. Starting from the 2,2-diphenyl-1,3-dioxolane derivative 1, previously shown to be a selective alpha(1a(A))/alpha(1d(D))-adrenoceptor subtype antagonist, over alpha(1b(B)) subtype and 5-HT(1A) receptor, and replacing one phenyl ring with lactam or imide moiety a reduction of alpha(1)/5-HT(1A) selectivity is observed, mainly due to the increase in 5-HT(1A) affinity. In functional experiments lactam derivatives seems to favour 5-HT(1A) receptor antagonism (pKb = 7.20-7.80) and alpha(1B)-adrenoceptor antagonist selectivity (alpha(1B)/alpha(1A) and alpha(1B)/alpha(1D) of about 10-fold). The most interesting of the various imide derivatives is compound 7t, which is a selective alpha(1D)-adrenoceptor antagonist (pKb = 8.1 and alpha(1D)/alpha(1A) and alpha(1D)/alpha(1B) selectivity ratios of 16 and 11 respectively) whereas at 5-HT(1A) receptor it is a potent partial agonist (pD2 = 7.98, E(max) = 60%).]. Given that cis and trans diastereomer pairs for 2-7 are possible, a computational strategy based on molecular docking studies was used to elucidate the atomic details of the 5HT(1A)/agonist and 5HT(1A)/antagonist interaction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic alpha-1 Receptor Agonists / chemical synthesis
  • Adrenergic alpha-1 Receptor Agonists / chemistry
  • Adrenergic alpha-1 Receptor Agonists / metabolism
  • Adrenergic alpha-1 Receptor Agonists / pharmacology
  • Adrenergic alpha-1 Receptor Antagonists / chemical synthesis
  • Adrenergic alpha-1 Receptor Antagonists / chemistry
  • Adrenergic alpha-1 Receptor Antagonists / metabolism
  • Adrenergic alpha-1 Receptor Antagonists / pharmacology
  • Animals
  • Dioxolanes / chemical synthesis
  • Dioxolanes / chemistry*
  • Dioxolanes / metabolism*
  • Dioxolanes / pharmacology
  • Humans
  • Imides / chemistry*
  • Lactams / chemistry*
  • Ligands
  • Male
  • Models, Molecular
  • Protein Binding
  • Protein Conformation
  • Rats
  • Receptor, Serotonin, 5-HT1A / chemistry
  • Receptor, Serotonin, 5-HT1A / metabolism*
  • Receptors, Adrenergic, alpha-1 / chemistry
  • Receptors, Adrenergic, alpha-1 / metabolism*
  • Serotonin 5-HT1 Receptor Agonists / chemical synthesis
  • Serotonin 5-HT1 Receptor Agonists / chemistry
  • Serotonin 5-HT1 Receptor Agonists / metabolism
  • Serotonin 5-HT1 Receptor Agonists / pharmacology
  • Serotonin 5-HT1 Receptor Antagonists / chemical synthesis
  • Serotonin 5-HT1 Receptor Antagonists / chemistry
  • Serotonin 5-HT1 Receptor Antagonists / metabolism
  • Serotonin 5-HT1 Receptor Antagonists / pharmacology
  • Stereoisomerism
  • Structure-Activity Relationship
  • Substrate Specificity

Substances

  • Adrenergic alpha-1 Receptor Agonists
  • Adrenergic alpha-1 Receptor Antagonists
  • Dioxolanes
  • Imides
  • Lactams
  • Ligands
  • Receptors, Adrenergic, alpha-1
  • Serotonin 5-HT1 Receptor Agonists
  • Serotonin 5-HT1 Receptor Antagonists
  • Receptor, Serotonin, 5-HT1A
  • formal glycol