ABSTRACT
The acetyl group of the muscarinic agonist aceclidine 4 was replaced by various 1,2,5-thiadiazoles to provide a new series of potent m1 muscarinic agonists 17 and 18. Optimal m1 muscarinic agonist potency was achieved when the 1,2,5-thiadiazole substituent was either a butyloxy, 17d, or butylthio, 18d, group. Although 1,2,5-oxadiazole 37 and pyrazine 39 are iso-pi-electronic with 1,2,5-thiadiazole 17d, both analogues were substantially less active than 17d. Compounds with high muscarinic affinity and/or m1 muscarinic agonist efficacy were also obtained when the 3-oxyquinuclidine moiety of 17d or 18c was replaced by ethanolamines, hydroxypyrrolidines, hydroxyazetidine, hydroxyisotropanes, or hydroxyazanorbornanes. The structure-activity data support the participation of the oxygen or sulfur atom in the substituent on the 1,2,5-thiadiazole in the activation of the m1 receptor. Several of these new 1,2,5-thiadiazoles have m1 agonist efficacy, potency, and selectivity comparable to those of xanomeline 2 in the muscarinic tests investigated.
Subject(s)
Muscarinic Agonists/chemistry , Muscarinic Agonists/pharmacology , Quinuclidines/chemistry , Quinuclidines/pharmacology , Thiadiazoles/chemistry , Animals , Brain/metabolism , Cell Line , Hydrolysis , Male , Mice , Models, Molecular , Muscarinic Agonists/metabolism , Phosphatidylinositols/metabolism , Quinuclidines/metabolism , Radioligand Assay , Rats , Rats, Sprague-Dawley , Static ElectricityABSTRACT
This report analyzes the relationship of hostile verbalizations to assaultive acts committed by 110 male schizophrenic patients on an acute psychiatric unit. It was found that patients who were verbally assaultive and threatening also tended to be physically assaultive. Assaults rarely occurred in the absence of verbal threats or abuse, and 32 per cent of violent patients could be identified on the basis of the occurrence of hostile verbalizations.
Subject(s)
Hospitalization , Hostility , Schizophrenic Psychology , Verbal Behavior , Violence , Acute Disease , Commitment of Mentally Ill , Humans , MaleABSTRACT
Data supporting the hypothesis that history of severe discipline and parental conflict in childhood is related to current violence were obtained in a study of 100 schizophrenic inpatients. In addition to a relation between inpatient violence and degree of schizophrenic symptoms, inpatient assaults and other dangerousness measures were positively and significantly correlated with severity of parental discipline, especially involving the father, and with degree of family conflict, particularly fights between parents and others outside the home.