Novel benzodioxan derivative, 5-[3-[((2S)-1,4-benzodioxan-2-ylmethyl) amino]propoxy]-1,3-benzodioxole HCl (MKC-242), with anxiolytic-like and antidepressant-like effects in animal models

J Pharmacol Exp Ther. 1996 Aug;278(2):898-905.

Abstract

Behavioral effects of MKC-242 (5-{3-[((2>)-1,4-benzodioxan-2-ylmethyl)amino] propoxy}-1,3-benzodioxole CHl), a novel and selective serotonin 1A receptor agonist, were investigated in rats and mice and compared against those of diazepam, buspirone and tandospirone. MKC-242 (0.0625-0.25 mg/kg, p.o.) significantly increased punished drinking in water-deprived rats. The reference compounds also increased punished drinking at doses of 10 to 40 mg/kg, p.o. The increase by MKC-242 was blocked by N-tert-butyl-3-(4-(2-methoxypenyl)piperazin-1-yl) -2-phenylpropanamide, a serotonin 1A receptor antagonist. MKC-242 (0.1-0.5 mg/kg, p.o.) also increased social interaction under high light and unfamiliar conditions in rats. It had weak benzodiazepine-like side effects in mice. MKC-242 (1, 3 mg/kg, p.o.) attenuated the reduction of locomotion caused by restraint stress in rats, the same effects were observed on both buspirone (100 mg/kg, p.o.) and tandospirone (100 mg/kg, p.o.). In the forced swimming test in rats, MKC-242 (0.3-3 mg/kg, i.p.), 8-hydroxy-2-(di-n-propylamino) tetralin (1, 3 mg/kg, i.p.) and amitriptyline (30 mg/kg, i.p.) reduced immobility, although diazepam, buspirone and tandospirone did not. The reduction by MKC-242 and 8-OH-DPAT was antagonized by N-tert-butyl-3-(4-(2-methoxyphenyl)piperazin-1-yl) -2-phenylpropanamide. Moreover, the reduction was also blocked by 1-(2--pyrimidinyl)piperazine (1-PP), a common metabolite of buspirone and tandospirone. These findings suggest that MKC-242 possesses potent anxiolytic and antidepressant properties that are mediated via an activation of serotonin 1A receptors.

MeSH terms

  • Animals
  • Buspirone / pharmacology
  • Dioxanes / pharmacology*
  • Dioxoles / pharmacology*
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drinking / drug effects*
  • Male
  • Mice
  • Mice, Inbred Strains
  • Motor Activity / drug effects
  • Rats
  • Rats, Wistar
  • Receptors, Serotonin / drug effects*
  • Serotonin Receptor Agonists / pharmacology*

Substances

  • Dioxanes
  • Dioxoles
  • Receptors, Serotonin
  • Serotonin Receptor Agonists
  • osemozotan
  • Buspirone