The antiemetic effects of six serotonergic 5-HT1A-receptor agonists, 8-hydroxy-2-(di-n-propylamino)tetrarin (8-OH-DPAT), 4-(4-[4-(2-pyrimidinyl)piperazin-1-yl]butyl)-2,3,4,5- tetrahydro-1,4-benzoxazepine-3,5-dione (SUN8399), buspirone, gepirone, ipsapirone and tandospirone, against motion sickness were investigated in Suncus murinus. Subcutaneous injection of all six agonists completely and dose-dependently suppressed motion-induced emesis. Pretreatment with 8-OH-DPAT or SUN8399 dose-dependently inhibited emesis elicited by nicotine (4.0 mg/kg, s.c.), veratrine (0.7 mg/kg, s.c.), cisplatin (20 mg/kg, i.p.) and copper sulfate (40 mg/kg, p.o.). These results suggest that serotonergic 5-HT1A-receptor agonists are effective as anti-motion sickness drugs, and these drugs may block a common mechanism(s) for the emetic reflex of the suncus because the antiemetic effects of the 5-HT1A-receptor agonists were exerted irrespective of the stimulus.

01 Jan 1994·Japanese Journal of Pharmacology

Effects of SUN 8399, a Potent and Selective 5-HT1A Agonist, on Conflict Behavior and Ambulatory Activity in Mice: Comparison with Those of Buspirone, Tandospirone and Diazepam

Article

Author: Kuribara, H

Behavioral effects of p.o. administration of SUN 8399, a selective 5-HT1A agonist, on the operant behavior under a MULT VI 1.5 min/FR 5-punishment schedule of food reinforcement and on the ambulatory activity were evaluated in mice, and the characteristics were compared with those of other 5-HT1A agonists, buspirone and tandospirone, and the benzodiazepine diazepam. Diazepam (3 and 10 mg/kg) significantly increased the punished response without eliciting any significant change in the non-punished response; i.e., showing anticonflict action. SUN 8399 (3-30 mg/kg) and buspirone (1-10 mg/kg) did not significantly change either the punished or non-punished responses. Tandospirone significantly increased the non-punished response at 10 mg/kg, but significantly decreased both the punished and non-punished responses at 30 mg/kg. The single administration of SUN 8399 (10 mg/kg), buspirone (3 and 30 mg/kg) and tandospirone (10 and 30 mg/kg) significantly increased the ambulatory activity, while diazepam tended to decrease it. The ambulation-increasing effect of methamphetamine (2 mg/kg, s.c.) was reduced by buspirone (10 and 30 mg/kg) and tandospirone (10 and 30 mg/kg), but enhanced by diazepam (3 and 10 mg/kg). Buspirone (30 mg/kg), tandospirone (10 and 30 mg/kg) and diazepam (3 and 10 mg/kg) significantly reduced the ambulation-increasing effect of scopolamine (0.5 mg/kg, s.c.). SUN 8399 (3-100 mg/kg) did not modify the effects of either methamphetamine or scopolamine. The present results suggest that 5-HT1A agonists scarcely show anticonflict action on the Geller-type conflict behavior in mice. However, SUN 8399 possesses different behavioral characteristics from those of the other two 5-HT1A agonists in terms of interactions with methamphetamine and scopolamine.

01 Jan 1993·Life SciencesQ3 · MEDICINE

Characterization of a cloned rat serotonin 5-HT1A receptor expressed in the HeLa cell line

Q3 · MEDICINE

Article

Author: Ichiro Sora ; Hiroaki Tomita ; Kenichi Kashihara ; Yutaka Fujiwara ; William R. Roeske ; Saburo Otsuki ; Yasutaro Hamagishi ; Mitsuru Hikiji ; Henry I. Yamamura ; Tetsuo Ohnuki ; Toshikazu Oki

We have previously isolated the rat serotonin (5-HT)1A receptor gene (G21Y2) and now report the expression and characterization of this receptor. The BamHI/Xbal fragment of this gene was cloned into Rc/RSV and stably transfected into HeLa cells by the calcium phosphate method. For determination of specific 5-HT1A receptor binding, [3H]8OH-DPAT was used as the radioligand and incubated with HeLa cell membranes. The cells expressed specific and saturable binding of [3H]8OH-DPAT with a Kd value of 0.3 nM and a Bmax value of 2 pmol/mg protein. GTP (50 microM) added to the incubation mixture increased the Kd value to 3 nM indicating that the expressed receptor is coupled to a G protein. The specific binding was inhibited by selective 5-HT1A partial agonists, such as buspirone, ipsapirone, gepirone, tandospirone, zalospirone and SUN8399 with Ki values of 1-30nM, whereas other neurotropic drugs except for spiperone (Ki = 46 nM) and nemonapride (Ki = 2.3 nM) were effective only at concentrations of more than 100 microM. The potencies of these compounds to inhibit [3H]8OH-DPAT from its specific binding sites were similar to their affinities determined in rat hippocampus binding studies. These data suggest that the expressed receptor is a 5-HT1A-type similar to 5-HT1A receptors in the rat hippocampus.

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Indication	Highest Phase	Country/Location	Organization	Date
Anxiety Disorders	Phase 1	-	Asubio Pharma Co. Ltd.	-
Anxiety Disorders	Phase 1	JP	Suntory Holdings Ltd.	-

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