piperidines and naxagolide

Blockade of D3 receptor, a member of the dopamine D2-like receptor family, has been suggested as a possible medication for schizophrenia. Blonanserin has high affinity in vitro for D3 as well as D2 receptors. We investigated whether a single dose of 12 mg blonanserin, which was within the daily clinical dose range (i.e., 8-24 mg) for the treatment of schizophrenia, occupies D3 as well as D2 receptors in healthy subjects.. Six healthy males (mean 35.7±7.6 years) received 2 positron emission tomography scans, the first prior to taking blonanserin, and the second 2 hours after the administration of a single dose of 12 mg blonanserin. Dopamine receptor occupancies by blonanserin were evaluated by [11C]-(+)-PHNO.. Occupancy of each region by 12 mg blonanserin was: caudate (range 64.3%-81.5%; mean±SD, 74.3±5.6%), putamen (range 60.4%-84.3%; mean±SD, 73.3%±8.2%), ventral striatum (range 40.1%-88.2%; mean±SD, 60.8%±17.1%), globus pallidus (range 65.8%-87.6%; mean±SD, 75.7%±8.6%), and substantia nigra (range 56.0%-88.7%; mean±SD, 72.4%±11.0%). Correlation analysis between plasma concentration of blonanserin and receptor occupancy in D2-rich (caudate and putamen) and D3-rich (globus pallidus and substantia nigra) regions showed that EC50 for D2-rich region was 0.39 ng/mL (r=0.43) and EC50 for D3-rich region was 0.40 ng/mL (r=0.79).. A single dose of 12 mg blonanserin occupied D3 receptor to the same degree as D2 receptor in vivo. Our results were consistent with previous studies that reported that some of the pharmacological effect of blonanserin is mediated via D3 receptor antagonism.

Topics: Adult; Antipsychotic Agents; Brain; Dopamine Agents; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Oxazines; Piperazines; Piperidines; Positron-Emission Tomography; Protein Binding; Radiopharmaceuticals; Receptors, Dopamine D2; Receptors, Dopamine D3

Evidence that tachykinin NK1 receptors selectively modulate activity in the mesolimbic dopamine pathway suggests an antipsychotic potential for tachykinin NK1 receptor antagonists. We investigated the ability of the antagonist CP-99,994 (and the less active enantiomer CP-100,263) to block dopamine receptor agonist-induced behaviour in guinea-pigs. The active dose range for inhibition of [Sar9,Met(O2)11]substance P-induced behaviour by CP-99,994 was 1-3 mg/kg s.c. The same doses of CP-100,263 were without effect. In contrast, both CP-99,994 (20 or 30 mg/kg) and CP-100,263 (10-30 mg/kg) antagonised behavioural stimulation induced by the dopamine receptor agonists amphetamine (1 mg/kg i.p.) or (+)-PHNO ((+)-4-propyl-9-hydroxy-naphthoxazine hydrochloride; 0.1 mg/kg s.c.). Lower doses of CP-99,994 or CP-100,263 were not active. These findings do not support the proposal that tachykinin NK1 receptors in the terminal projection area of the mesolimbic system can modify dopamine-mediated behaviour.

Topics: Amphetamine; Analysis of Variance; Animals; Behavior, Animal; Dopamine Agonists; Grooming; Guinea Pigs; Haloperidol; Injections, Intraperitoneal; Injections, Subcutaneous; Male; Motor Activity; Neurokinin A; Neurokinin-1 Receptor Antagonists; Oxazines; Piperidines; Receptors, Neurokinin-1; Stereoisomerism; Substance P