ABSTRACT
New antipsychotic drugs are needed because current therapy is ineffective for many schizophrenics and because treatment is often accompanied by extrapyramidal symptoms and dyskinesias. This paper describes the design, synthesis, and evaluation of a series of related (aminomethyl)benzamides in assays predictive of antipsychotic activity in humans. These compounds had notable affinity for dopamine D2, serotonin 5-HT1A, and alpha1-adrenergic receptors. The arylpiperazine 1-[3-[[4-[2-(1-methylethoxy)phenyl]-1-piperazinyl]methyl]benzoyl]p ipe ridine (mazapertine, 6) was chosen because of its overall profile for evaluation in human clinical trials. The corresponding 4-arylpiperidine derivative 67 was also highly active indicating that the aniline nitrogen of 6 is not required for activity. Other particularly active structures include homopiperidine amide 14 and N-methylcyclohexylamide 31.
Subject(s)
Antipsychotic Agents , Piperazines , Piperidines , Receptors, Adrenergic, alpha-1/metabolism , Receptors, Dopamine D2/metabolism , Receptors, Serotonin/metabolism , Adrenergic Agents/chemical synthesis , Adrenergic Agents/chemistry , Adrenergic Agents/metabolism , Adrenergic Agents/pharmacology , Animals , Antipsychotic Agents/chemical synthesis , Antipsychotic Agents/chemistry , Antipsychotic Agents/metabolism , Antipsychotic Agents/pharmacology , Avoidance Learning/drug effects , Catalepsy/chemically induced , Cerebral Cortex/metabolism , Conditioning, Psychological/drug effects , Corpus Striatum/metabolism , Dopamine Agents/chemical synthesis , Dopamine Agents/chemistry , Dopamine Agents/metabolism , Dopamine Agents/pharmacology , Humans , Male , Piperazines/chemical synthesis , Piperazines/chemistry , Piperazines/metabolism , Piperazines/pharmacology , Piperidines/chemical synthesis , Piperidines/chemistry , Piperidines/metabolism , Piperidines/pharmacology , Rats , Rats, Sprague-Dawley , Rats, Wistar , Receptors, Serotonin, 5-HT1 , Serotonin Agents/chemical synthesis , Serotonin Agents/chemistry , Serotonin Agents/metabolism , Serotonin Agents/pharmacology , Structure-Activity RelationshipSubject(s)
Guanidines/chemical synthesis , Peptides/chemical synthesis , Thiazoles/chemical synthesis , Thrombin/antagonists & inhibitors , Amino Acid Sequence , Animals , Arginine/analogs & derivatives , Binding Sites , Cattle , Crystallography, X-Ray , Guanidines/chemistry , Guanidines/pharmacology , Humans , Molecular Sequence Data , Molecular Structure , Oligopeptides/pharmacology , Peptides/chemistry , Peptides/pharmacology , Pipecolic Acids/pharmacology , Protein Binding , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacology , Sulfonamides , Thiazoles/chemistry , Thiazoles/pharmacology , Thrombin/chemistry , Trypsin Inhibitors/chemical synthesis , Trypsin Inhibitors/chemistry , Trypsin Inhibitors/pharmacologyABSTRACT
Two herds of beef cattle were maintained beneath a +/- 500 kV direct-current transmission line during a 30-month period, and were compared with two similar herds maintained away from the transmission line. Exposures of animals under the line were five to 30 times greater than those of control animals, depending on the parameter of interest, with average exposure magnitudes of 5.6 kV/m, 4.1 nA/m2, and 13 k ions/cm3, respectively, for electric field, ion current, and density of ions. Productivity and health status of cows and calves were similar between lines and control treatments. Mean body mass of cows increased with maturity, from 438 kg in 1985 to 496 kg in 1987. Calf gain averaged 0.93 kg per head per day. No unusual sources of mortality were observed. Based on this confinement study, beef cattle permitted to graze in the vicinity of a high-voltage, direct-current transmission lines are not expected to experience any decrease in frequency of conception, calving, growth rate, or survival.
