Antianxiety Properties Research Articles

ChemInform Abstract: 1‐AZACYCLOALKYL‐1,4‐BENZODIAZEPIN‐2‐ONES WITH ANTIANXIETY‐ANTIDEPRESSANT ACTIONS

A series of 1-azacycloalkyl-1,4-benzodiazepin-2-ones were synthesized from 1-azacycloalkyl-2-benzoylanilines and corresponding imines and then evaluated for their central nervous system activities. Pharmacological data showed that some of these compounds have potent antidepressant properties, as assessed by their antagonism of tetrabenzine (TBZ) induced ptosis and their inhibition of [3H]norepinephrine uptake into rat brain synaptosomes, as well as their moderate antianxiety properties of preventing of pentylenetetrazol (PTZ) convulsion, suppressing conflict behavior, and displacing potential for [3H]diazepam binding. Introduction of a halogen substituent at position 7 of the 1,4-benzodiazepine ring lengthened the anti-PTZ effects, although the peak effect was slightly reduced and clearly enhanced the anti-PTZ and anticonflict properties. Introduction of Cl to the ortho position of the phenyl ring at position 5 greatly reduced the antidepressant properties. The secondary amine function of the azacyclic ring at position 1 was essential for the production of the antidepressant properties. Of these new series, 7-fluoro-5-(2-fluorophenyl)-1,3-dihydro-1-(4-piperidinyl)-2H-1,4-benzodi azepin-2 -one has the potential to become a useful antidepressant drug with a moderate antianxiety property.

1-Azacycloalkyl-1,4-benzodiazepin-2-ones with antianxiety-antidepressant actions.

A series of 1-azacycloalkyl-1,4-benzodiazepin-2-ones were synthesized from 1-azacycloalkyl-2-benzoylanilines and corresponding imines and then evaluated for their central nervous system activities. Pharmacological data showed that some of these compounds have potent antidepressant properties, as assessed by their antagonism of tetrabenzine (TBZ) induced ptosis and their inhibition of [3H]norepinephrine uptake into rat brain synaptosomes, as well as their moderate antianxiety properties of preventing of pentylenetetrazol (PTZ) convulsion, suppressing conflict behavior, and displacing potential for [3H]diazepam binding. Introduction of a halogen substituent at position 7 of the 1,4-benzodiazepine ring lengthened the anti-PTZ effects, although the peak effect was slightly reduced and clearly enhanced the anti-PTZ and anticonflict properties. Introduction of Cl to the ortho position of the phenyl ring at position 5 greatly reduced the antidepressant properties. The secondary amine function of the azacyclic ring at position 1 was essential for the production of the antidepressant properties. Of these new series, 7-fluoro-5-(2-fluorophenyl)-1,3-dihydro-1-(4-piperidinyl)-2H-1,4-benzodi azepin-2 -one has the potential to become a useful antidepressant drug with a moderate antianxiety property.

The Use of Beta‐Adrenergic Blocking Agents in Anxiety Disorders and Schizophrenia

In the 1960s, several studies reported that propranolol and other beta-blocking drugs appeared especially useful in patients with physical symptoms of anxiety. However, subsequent reports produced conflicting findings, and at this time the efficacy of propranolol in anxiety disorders is not clearly established. Propranolol's utility in anxiety states may be entirely restricted to those anxiety patients whose physical symptoms have not adequately responded to benzodiazepine therapy. This places the beta-blockers among the least useful drugs in treating anxiety disorders. A major problem in assessing propranolol's antianxiety properties has been a virtual lack of well-designed studies addressing the issue; the studies reviewed here contained a surprising number of study design problems. Several guidelines regarding study design are included to assist the reader in evaluating studies of antianxiety agents. High dose (e.g., 2,000 mg) propranolol may have a role as an alternative to traditional antipsychotic therapy in neuroleptic-resistant patients. During the last decade a number of studies have demonstrated symptomatic improvement in schizophrenic patients using propranolol alone or combined with neuroleptics. However, four recent double-blind reports have failed to replicate this finding. Future research should focus on possible identification of propranolol-responsive patients and their characteristics. The use of propranolol and other beta-blockers in schizophrenia should remain in the research or medical center setting.

The Use of Beta‐Adrenergic Blocking Agents in Anxiety Disorders and Schizophrenia

In the 1960s, several studies reported that propranolol and other beta‐blocking drugs appeared especially useful in patients with physical symptoms of anxiety. However, subsequent reports produced conflicting findings, and at this time the efficacy of propranolol in anxiety disorders is not clearly established. Propranolol's utility in anxiety states may be entirely restricted to those anxiety patients whose physical symptoms have not adequately responded to benzodiazepine therapy. This places the beta‐blockers among the least useful drugs in treating anxiety disorders. A major problem in assessing propranolol's antianxiety properties has been a virtual lack of well‐designed studies addressing the issue; the studies reviewed here contained a surprising number of study design problems. Several guidelines regarding study design are included to assist the reader in evaluating studies of antianxiety agents.High dose (e.g., 2,000 mg) propranolol may have a role as an alternative to traditional antipsychotic therapy in neuroleptic‐resistant patients. During the last decade a number of studies have demonstrated symptomatic improvement in schizophrenic patients using propranolol alone or combined with neuroleptics. However, four recent double‐blind reports have failed to replicate this finding. Future research should focus on possible identification of propranolol‐responsive patients and their characteristics. The use of propranolol and other beta‐blockers in schizophrenia should remain in the research or medical center setting.

2-Benzazepines. 4. [1,2,3]Triazolo[4,5-d][2]benzazepines and dibenzo[c,f][1,2,3]triazolo[3,4-a]azepines: synthesis and evaluation as central nervous system agents.

The facile synthesis of [1,2,3]triazolo((4,5-d][2]benzazepines and dibenzo[c,f][1,2,3]triazolo[3,4-a]azepines by the addition of sodium azide to acetylenic benzophenones is described. Examination of the pharmacological data indicates that selected triazolobenzazepines are as potent as diazepam in the anti-pentylenetetrazole test and are weaker in the inclined screen and rotarod tests, suggesting that these compounds have antianxiety properties similar to diazepam with fewer deficits in motor coordination. In addition, a possible diazepam antagonist was found in the triazolo-benzazepine series. The dibenzotriazoloazepines were found to be inactive in four standard CNS screening procedures.

Determination of anticholinesterases in tissues

Studies on pharmacotherapy for anxiety continue to evolve along the dual paths of agents and actions. While benzodiazepines (BZs) continue to be the agents of choice for anxiolysis, new series of non-BZ compounds are emerging that may offer alternatives in the management of anxiety disorders. Continuing efforts, at both the molecular and animal model level, to understand the BZ receptor binding, the actions of endogenous ligands, and the properties of BZ antagonists provide new insight into the mechanisms of action of the agents with anti-anxiety properties. The dynamic interchanges between preclinical pharmacology and clinical verification of anti-anxiety efficacy continue to define the science of anxiolysis. The hypnotic effects of different BZs and their related pharmacokinetics have been a matter of interest. A model of insomnia induced by methylphenidate and caffeine has been used in the evaluation of temazepam. The thienodiazepine, brotizolam, proved superior to flurazepam in the treatment of chronic insomnia and studies continue to document the hypnotic efficacy of quazepam. The safety and efficacy of triazolam versus nitrazepam is discussed in the chapter. While triazolam usually appeared to be the subjective preference, no significant differences existed between the two in their side effect profiles. The in vivo effects and potential biochemical mechanisms, structure–activity relationships, and gamma-aminobutyric acid (GABA) receptor interactions of barbiturates, and the interactions of various barbiturates with BZ receptors have been studied; barbiturate enhancement of GABA binding correlated with the anesthetic activity of the studied compounds. A clinical study of the hypnotic activity of zopiclone showed it to have favorable effects on sleep with neither the impairment of performance nor interaction with alcohol. The significant sedative effects of adenosine analogues appear to be mediated by mechanisms different than that of the BZs. As for anti-convulsant, structure–activity relationships have been discussed in the chapter. Several clinical evaluations of valproic acid and a possible role for both prostaglandins and opioid peptides as endogenous anti-convulsants have been discussed in the chapter.

Schedule Dependent Change of Punished Responding After Diazepam in Rats

It has been considered that, in the preclinical drug assay, punishment experiment is one of the best methods to evaluate an anti-anxiety property of psychotropic drugs. Many groups (1–7) have reported that anti-anxiety drugs increase the punished responding. In the punishment experiment, differences of the experimental situations, such as schedule programming, reinforcer and drug experience of the experimental animal etc. may affect the change of punished responding after the drugs. However, few systematic studies concerning these basic methodological problems have been done. In the present work, we examined the effect of diazepam on the three types of conditioned response-suppression which were produced under the fixed ratio (FR30) schedule of food and/or water reinforcements.

Schedule dependent change of punished responding after diazepam in rats.

It has been considered that, in the preclinical drug assay, punishment experiment is one of the best methods to evaluate an anti-anxiety property of psychotropic drugs. Many groups (1–7) have reported that anti-anxiety drugs increase the punished responding. In the punishment experiment, differences of the experimental situations, such as schedule programming, reinforcer and drug experience of the experimental animal etc . may affect the change of punished responding after the drugs. However, few systematic studies concerning these basic methodological problems have been done. In the present work, we examined the effect of diazepam on the three types of conditioned response-suppression which were produced under the fixed ratio (FR30) schedule of food and/or water reinforcements.

Relationship of plasma levels of chlordiazepoxide and metabolites to clinical response

The authors report on the relationship between the antianxiety effects of chronically administered chlordiazepoxide (CDX) and plasma levels of CDX and two of its metabolites, desmethylchlordiazepoxide (DMCDX) and demoxepam (DMX). Fifteen subjects with moderate to severe anxiety were studied in a double-blind, placebo-controlled, crossover design. Significant correlations were found between anxiety reduction and DMCDX and DMX plasma levels. No such correlation was observed between anxiety reduction and CDX levels. These data suggest that in chronically treated subjects, DMCDX and DMX have significant antianxiety properties which surpass those of CDX itself.

Apnea After Intravenous Diazepam Therapy

DIAZEPAM, a benzodiazepine derivative, is widely used for its antianxiety, anticonvulsant, psychosedative, amnesiac, and muscle-relaxing properties. Intravenous diazepam is extensively used as an anesthetic induction agent, as an adjunct for procedures such as cardioversion and endoscopy, and as a supplement to regional or local anesthesia. Although diazepam is generally considered to be an unusually safe drug, a variety of side effects have been reported. 1,2 We report a potentially fatal complication following intravenous administration of diazepam. Report of a Case A 56-year-old man was scheduled for spermatocele repair under local anesthesia. The patient had been admitted for chest pain and shortness of breath two weeks prior to the surgery, but examination by physicians on the medical service showed no noteworthy changes in his ECGs or cardiac enzyme levels. Chest roentgenograms, arterial blood gas values, and a lung scan were within normal limits. Pulmonary function tests showed mild obstructive disease. The

ChemInform Abstract: 3‐HALO‐5,7‐DIMETHYLPYRAZOLO(1,5‐A)PYRIMIDINES, A NONBENZODIAZEPINOID CLASS OF ANTIANXIETY AGENTS DEVOID OF POTENTIATION OF CENTRAL NERVOUS SYSTEM DEPRESSANT EFFECTS OF ETHANOL OR BARBITURATES

AbstractZu Untersuchungen der Wirkung auf das Zentralnervensystem werden Verbindungen der allgemeinen Formel (I) nach bekannten Verfahren mit guten Ausbeuten hergestellt und in Tabellen aufgeführt.

Prazepam in anxiety: A controlled clinical trial

Prazepam, a benzodiazepine derivative similar in chemical structure and biological activity to diazepam and chlordiazepoxide, has been reported in the literature to possess antianxiety properties in daily doses of up to 80 mg/day. Shaffer et al. 1 found 40–80 mg/day prazepam more effective than placebo but not chlordiazepoxide, in relief of postwithdrawal anxiety in alcoholics. Studies with anxious outpatient psychoneurotics have shown prazepam to be more effective than placebo and equally effective to chlordiazepoxide. For example Silver et al. 2 found prazepam 30–60 mg superior to chlordiazepoxide and placebo in overall efficacy at 4 weeks but not at 2 weeks, while Dunlop and Weisberg 3 reported similar results with 30–60 mg at an endpoint of 4 or 6 weeks. The present 4 week double-blind study was undertaken to help determine the optimum daily dosage of prazepam. To this end the study was designed not only to test the efficacy of 2 daily dosage regimens of prazepam, i.e., 40 and 60 mg, but also to make use of its relatively long half-life by administering it once daily at bedtime.

Effects of naloxone on experimentally induced ischemic pain and on mood in human subjects.

The hypothesis that painful stimuli activate the endogenous opioid (endorphin) system in humans was tested by examining the effect of the opiate antagonist naloxone on experimentally induced ischemic pain and on subjective mood ratings. Intravenous injections of saline or naloxone hydrochloride (2 and 10 mg) were administered under double-blind conditions to 12 subjects. Naloxone did not affect the pain ratings. However, a significant dose-related effect of naloxone on tension-anxiety was found, suggesting that the endorphins. like exogenously administered opiates, may have antianxiety properties.

Comparison between chronic chlordiazepoxide treatment and shock removal in a conflict situation in rats

The different psychopharmacological actions of chlordiazepoxide were analyzed using a conflict schedule and chronic administration of the drug. The effects of foot shock removal and drug treatment were compared. Individual variance in the rat population was also examined. The 20 min schedule consisted of alternating 5 min periods of fixed-ratio 10 and continuous reinforcement plus shock schedules, which is a conflict situation. Chronic treatment with chlordiazepoxide (4 mg/kg i.p. for 16 days) and with foot shock removal (for 9 days) significantly increased response rate during the conflict situation. Shock removal produced a much higher rate of response. Individual rates of responding were much less varied during the shock removal period than during the period with a fixed level of foot shock (0·4 mA, 1 sec). Animals which were less depressed by foot shocks showed a higher rate of responding with chlordiazepoxide treatment. Qualitative differences between chlordiazepoxide and shock removal treatment revealed the well established anti-anxiety properties and effects which increase lever-pressing rates.

Effects of propranolol and chlordiazepoxide on conflict behavior in rats.

Clinical reports have suggested that propranolol, a Β-adrenergic blocker, has antianxiety properties. In the present laboratory experiments, this suggestion was explored by testing propranolol and chlordiazepoxide in rat lever-pressing conflict procedures that selectively identify antianxiety compounds. Chlordiazepoxide produced anticonflict effects in such a procedure at doses from 1.25 to 40 mg/kg. Propranolol, tested at doses of 2.5 to 80 mg/kg, did not produce the anticonflict pattern typical of standard antianxiety agents, which is characterized by progressive dose-related increases in punished responding that frequently are several 100% above control levels. In contrast, the largest increases produced by propranolol, which occurred in the 10–40 mg/kg dose range, were 18–26% above control; only the 26% increase observed at the 20 mg/kg dose was statistically significant. In a different conflict test, a 40 mg/kg dose of propranolol was found to have a slight, but not significant, anticonflict effect. When this dose level was combined with doses of 2.5, 5, or 10 mg/kg of chlordiazepoxide p.o., the combined treatments produced greater anticonflict effects than did the corresponding individual doses of chlordiazepoxide.