[1,2,4]Triazole derivatives as 5-HT(1A) serotonin receptor ligands

Bioorg Med Chem. 2002 Feb;10(2):313-23. doi: 10.1016/s0968-0896(01)00281-4.

Abstract

A series of new 4-amino-3-[3-[4-(2-methoxy or nitro phenyl)-1-piperazinyl] propyl]thio]-5-(substitutedphenyl)[1,2,4]triazoles 11a-t was synthesized in order to obtain compounds with high affinity and selectivity for 5-HT(1A) receptor over the alpha(1)-adrenoceptor. A series of isomeric 4-amino-2-[3-[4-(2-methoxy or nitro phenyl)-1-piperazinyl]propyl]-5-(substitutedphenyl)-2,4-dihydro-3H[1,2,4]triazole-3-thiones 12a-r was also isolated and characterized. New compounds were tested to evaluate their affinity for 5-HT(1A) receptor and alpha(1)-adrenoceptor in radioligand binding experiments. As a general trend, triazoles 11a-t showed a preferential affinity for the 5-HT(1A) receptor whereas isomeric 2,4-dihydro-3H[1,2,4]triazole-3-thiones 12a-r preferentially bind to the alpha(1)-adrenoceptor site. Several molecules showed affinities in the nanomolar range and 4-amino-3-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]thio]-5-(4-propyloxy-phenyl)[1,2,4]triazole (11o) was the most selective derivative for the 5-HT(1A) receptor (K(i) alpha(1)/K(i) 5-HT(1A)=55). The decrease in 5-HT(1A) receptor selectivity in 3-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]thio]-5-(substitutedphenyl)[1,2,4] triazole 14a-b, lacking in the amino group in 4-position of the triazole ring, in comparison with their analogues in the series 11a-t, suggest that the amino function represents a critical structural feature in determining 5-HT(1A) receptor selectivity in this class of compounds.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biochemistry / methods
  • Drug Evaluation, Preclinical / methods
  • Ligands
  • Male
  • Rats
  • Rats, Inbred Strains
  • Receptors, Adrenergic, alpha-1 / drug effects
  • Receptors, Adrenergic, alpha-1 / metabolism
  • Receptors, Dopamine D2 / drug effects
  • Receptors, Dopamine D2 / metabolism
  • Receptors, Serotonin / metabolism*
  • Receptors, Serotonin, 5-HT1
  • Structure-Activity Relationship
  • Thiones / chemistry*
  • Thiones / metabolism*
  • Triazoles / chemistry*
  • Triazoles / metabolism*

Substances

  • Ligands
  • Receptors, Adrenergic, alpha-1
  • Receptors, Dopamine D2
  • Receptors, Serotonin
  • Receptors, Serotonin, 5-HT1
  • Thiones
  • Triazoles