Analysis of tandospirone (SM-3997) interactions with neurotransmitter receptor binding sites.
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-HT1A receptor, displaying a Ki value of 27 +/- 5 nM. The agent is approximately two to three orders of magnitude less potent at 5-HT2, 5-HT1C, alpha 1-adrenergic, alpha 2-adrenergic, and dopamine D1 and D2 receptors (Ki values ranging from 1300 to 41000 nM). Tandospirone is essentially inactive at 5-HT1B 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-HT1A receptor binding sites in rat cortical membranes (KD = 4.5 +/- 0.8 nM; Bmax = 2.2 +/- 0.6 pmol/g tissue). Based on adenylate cyclase studies which measure 5-HT1A receptor-mediated effects, tandospirone displays approximately 60% of the agonist effect of 8-OH-DPAT, a selective 5-HT1A agonist. Thus, the primary pharmacological effect of tandospirone appears to be partial agonism at the 5-HT1A receptor, an activity similar to other pyrimidinyl-piperazines which are being developed as novel anxiolytic agents.
Hamik
A
A
Department of Neurology, Stanford University Medical Center, CA 94305.
Oksenberg
D
D
Fischette
C
C
Peroutka
S J
SJ
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D014151:Anti-Anxiety Agents / Q000493:pharmacokinetics*; D001667:Binding, Competitive / Q000502:physiology; D001921:Brain / Q000201:enzymology*; D002065:Buspirone / Q000493:pharmacokinetics; D054833:Isoindoles; D008297:Male; D010879:Piperazines / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000493:pharmacokinetics*; D011869:Radioligand Assay; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D011954:Receptors, Dopamine / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism*
D014151:Anti-Anxiety Agents; D054833:Isoindoles; D010879:Piperazines; D011743:Pyrimidines; D011942:Receptors, Adrenergic, alpha; D011943:Receptors, Adrenergic, beta; D011954:Receptors, Dopamine; D011985:Receptors, Serotonin; C055267:tandospirone; C043077:ipsapirone; D000262:Adenylyl Cyclases; C039979:gepirone; D002065:Buspirone