Preclinical neurochemical and electrophysiological profile of 1192U90, a potential antipsychotic.
11192U90 was submitted to receptor binding and monoamine uptake assays. It bound potently at serotonin 5-HT2, dopaminergic D2, serotonin 5-HT1A, and adrenergic alpha 1 and alpha 2 receptors. It also bound to dopaminergic D1, serotonin 5-HT3, serotonin 5-HT4, and sigma sites, albeit with lower affinity. It was essentially inactive at 22 other sites, including those for cholinergic M1 and M2. It weakly inhibited uptake of 3H-norepinephrine, 3H-serotonin and 3H-dopamine. Acute doses of 1192U90 (5 and 20 mg/kg P.O.) increased whole-brain levels of dopamine metabolites but did not affect levels of norepinephrine, dopamine, and serotonin. Subcutaneous injection of 1192U90 (0.8 mg/kg/day) and clozapine (20 mg/kg/day) for 28 days preferentially decreased the number of spontaneously active dopamine cells in the ventral tegmental area (VTA) but not the substantia nigra (SN) of rats, as measured by population sampling. This outcome is characteristics of atypical antipsychotics like clozapine. Acute injections of 1192U90 reversed the rate-inhibiting effects of microiontophoretically applied dopamine and intravenously injected apomorphine and d-amphetamine on dopamine cell firing. Intravenous injection or iontophoretic application of 1192U90 or the 5-HT1A agonist (+/-)8-OH-DPAT inhibited the firing rates of dorsal raphe nucleus (DRN) neurons in rats, and the effects of both compounds were blocked by iontophoretically applied S(-) propranolol, a 5-HT1A antagonist. The results suggest that 1192U90 is a preferential dopamine D2 antagonist as well as a 5-HT1A agonist that may prove to be an atypical antipsychotic.
Jones-Humble
S A
SA
Pharmacology Division, Burroughs Wellcome Co., Research Triangle Park, NC 27709, USA.
Durcan
M J
MJ
Lyerly
D
D
Norton
R M
RM
Tang
F L
FL
Russell
A V
AV
Watson
M J
MJ
Gengo
P J
PJ
Morgan
P F
PF
Wang
C M
CM
Cooper
B R
BR
Cox
R F
RF
D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000378:metabolism*; D001058:Apomorphine / Q000494:pharmacology; D001679:Biogenic Amines / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000502:physiology; D003024:Clozapine / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010879:Piperazines / Q000378:metabolism* / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D013844:Thiazoles / Q000378:metabolism* / Q000494:pharmacology
D014150:Antipsychotic Agents; D001679:Biogenic Amines; D010879:Piperazines; D013844:Thiazoles; C098658:1192U90; D000661:Amphetamine; D003024:Clozapine; D001058:Apomorphine