Analysis of tandospirone (SM-3997) interactions with neurotransmitter receptor binding sites

Abstract

The interactions of tandospirone (formerly called SM-3997) with 5-HT and other neurotransmitter receptor binding sites were determined in brain homogenates. Tandospirone is most potent at the 5-HT_1A receptor, displaying a K₁ value of 27 ± 5 nM. The agent is approximately two to three orders of magnitude less potent at 5-HT₂, 5-HT_1c, alpha₁- adrenergic, alpha₂-adrenergicm and dopamine D₁ and D₂ receptors (K₁ values ranging from 1300 to 41000 nM). Tandospirone is essentially inactive at 5-HT_1B receptors; 5-HT uptake sites; beta-adrenergic, muscarinic cholinergic, and benzodiazepine receptors. This pharmacological profile differs slightly from that of other novel anxiolytics such as buspirone, ipsapirone, and gepirone, Saturation and competition studies using ³H-tandospirone also suggest that the drug interacts with 5-HT_1A receptor binding sites in rat cortical membranes (K_D = 4.5 ± 0.8 nM;B_max = 2.2 ± 0.6 pmol/g tissue). Based on adenylate cyclase studies which measure 5-HT_1A receptor-mediated effects, tandospirone displays approximately 60% of the agonist effect of 8-OH-DPAT, a selective 5-HT_1A agonist. Thus, the primary pharmacological effect of tandospirone appears to be partial agonism at the 5-HT_1A receptor, an activity similar to other pyrimidinyl-piperazines which are being developed as novel anxiolytic agents.