108
Pharmacological and Behavioral Proriie of Alpidem as an Anxiolytic B. Zivkovic. E. Morel, D. Joly, Gh. Perrault, D. J. Sanger. K. G. Lloyd Synthelabo Recherche (L.E.R.S.), Bagneux, France
Pharmacological and behavioral studies in mice and rats have shown that the imidazopyridine alpidem possesses anxiolytic activity with a profile which is substantially different from that of benzodiazepines. Thus, in mice, alpidem inhibited marble-burying behavior and enhanced feeding under stressful conditions, as did benzodiazepines; in contrast to these drugs, however, alpidem was inactive against shock-induced fighting and shock-suppressed exploration. In rats, alpidem exerted anticonflict activity in the punished drinking test, but failed to antagonize punishmentinduced inhibition of operant behavior. Moreover, in rats trained to discriminate chlordiazepoxide from saline, alpidem did not produce a benzodiazepine-like interoceptive stimulus. Alpidem also produced anticonvulsant effects in a variety of tests sensitive to benzodiazepines. However, the order of potencies against convulsions induced by different convulsive agents was different from that of the benzodiazepines. Alpidem decreased motor performance in the rotarod test and only produced a deficit in muscle strength at doses which were more than 20 times higher than the doses active in anxiolytic tests. Moreover, alpidem did not interfere with the acquisition of conditioned fear, except at very high doses, indicating a weak potential to impair memory. The effects of alpidem were antagonized by f1umazenil, indicating that centtal omega receptors are involved in the action ofthis drug. The weak sedative effects of alpidem may be attributed to its low intrinsic activity, as demonstrated by its low efficacy in increasing latency to isoniazid-induced convulsions.
Pharmacopsychiatry 23 (1990) 108-113 (Supplement) © GeorgThieme Verlag Stuttgart· New York
Das pharmakologische und VerhaltensprofJJ von Alpidem als Anxiolytikum Pharmakologische und Verhaltensstudien bei Mäusen und Ratten haben gezeigt, daß das Imidazopyridin Alpidem eine anxiolytische Wirksamkeit mit einem Wirkungsprofil besitzt, das sich grundlegend von dem der Benzodiazepine unterscheidet. Bei Mäusen hemmte Alpidem beispielsweise den Trieb, Murmeln zu horten, und verstärkte das Freßverhalten bei Streßzuständen, was auch die Benzodiazepine taten, dagegen blieb Alpidem unwirksam gegenüber schockinduziertem Kampfverhalten und schockunterdfÜcktem Erforschungsdrang, im Gegensastz zu der Wirkung der Benzodiazepine. Bei Ratten übte Alpidem eine Antikonfliktwirkung beim bestraften Trinktest aus, bewirkte jedoch keinen antogonistischen Effekt gegen bestrafungsinduzierte Hemmung des Verhaltens gegenüber operanten Interventionen. Außerdem erzeugte Alpidem bei Ratten, die gelernt hatten zwischen Chlordiazepoxid und Kochsalzlösung zu unterscheiden, keinen benzodiazepinähnlichen interozeptiven Reiz. Alpidem erzeugte auch antikonvulsivischeWirkungen in einer Reihe von Tests, die gegen Benzodiadepine empfindlich waren. Die Rangfolge der Wirkungsstärke gegen Konvulsionen, die durch verschiedene Kunvulsiva ausgelöst wurden, utnerschied sich von derjenigen der Benzodiazepine. Alpidem setzte die motorische Bewegung beimRotastabtest herab und erzeugte ein Defizit der Muskelstärke erst bei Dosierungen, die um das 20fache über den anxiolytisch wirksamen Dosierungen lagen. Außerdem übte Alpidem bis zu sehr hohen Dosierungen keine WIrkung auf das Erlernen konditionierter Angst aus, was auf ein schwaches Potential hinsichtlich einer gedächtnishemmenden Wirkung hindeutet. Flumazenil zeigte einen Antagonismus gegen die Wirkungen von Alpidem, woraus geschlossen werden kann, daß der Wirkungsmechanismus von Alpidem mit zentralen Omegarezeptoren in Zusammenhang gebracht werden kann. Die schwach sedierende Wirkung des Alpidem kann auf seiner geringen Intrinsic Activity beruhen, wie sein niedriger Wirkungsgrad hinsichtlich einer Verlängerung der Latenz von isoniazidinduzierten Konvulsionen zeigt.
Downloaded by: University of Iowa Libraries. Copyrighted material.
Summary
Pharmacopsychiatry 23 (1990)
Pharmacological and Behavioral Profile 01Alpidem as an Anxiolytic
109
Table 1 Activity of alpidem, chlordiazepoxide, and diazepam in animal models of anxiolytic activity Minimum effective dose (mg/kg p.o.) Alpidem Chlordiazepoxide
Marble-burying in mice Stimulation of food intake - in mice - in rats Shock-induced fighting in mice Four-plate test in mice Y-maze in mice Staircase test in rats Punished leverpressing in rats
Diazepam
10
30
3
10 20 inactive up to 60 inactive 1 30 inactive up to 80 (ip)
10 20 10
3
Introduction Benzodiazepines are higWy effective in alleviating symptoms of different forms of anxious states, and for this reason these drugs are currently central to the therapy of anxiety. In addition to their anxiolytic action, benzodiazepines also exert anticonvulsant, myorelaxant, and sedative effects (Randa/l et al., 1974). All of these effects appear to be related to the same receptor mechanism and it is often difficult to determine the dose which would induce c1inically useful anxiolytic effects in the absence of other (e.g., myorelaxant or sedative) effects. As these latter effects may severe1y interrupt daily activities, there is c1early a need for anxiolytics devoid of these side-effects. Following the discovery of receptors involved in the action of benzodiazepines, serious efforts have been made to find compounds of a nonbenzodiazepine structure which would act through a similar mechanism (Williams, 1984). Among these new structures, some ofthe most promising compounds for c1inical use belong to the imidazo(l,2a)pyridine family which show high affinity for the omega receptor subtypes (Dimsdale et al., 1988), and ofwhich zolpidem (Stilnox(!l) has proved to be an effective hypnotic with numerous advantages over benzodiazepines (Nicholson and Pascoe, 1985; Monti, 1989). The present paper describes the neuropharmacological and behavioral effects of alpidem, another imidazo(I,2-a)pyridine which has been developed as an anx.iolytic agent.
3
10 3 30 3 (ip)
0.3 20 3 (ip)
Alpidem was also active in aseries of behavioral tests performed in rats. Here, for example, alpidem's potency in increasing food consumption in rats habituated to eating their total daily food requirements within four hours, was similar to that of chlordiazepoxide. Alpidem also decreased rearing activity, measured in an experimental chamber equipped with a staircase. While benzodiazepines produced a similar effect, low doses of these drugs, unlike alpidem, also increased exploratory activity. The biggest differences between alpidem and benzodiazepines, however, were observed in experimental procedures involving operant behavior. In punishment (contlict) procedures, in which rats are trained to press alever for food reward, benzodiazepines increase the rate of lever pressing during periods in which this behaviour is suppressed by electric shock punishment. This occurs at doses which have little effect on unpunished lever pressing (Cook and Davidson, 1973). Alpidem failed to produce any significant increase in the rate of lever pressing during punished periods, but when administered at relatively high doses it decreased the number of lever presses during the unpunished periods. These results cannot simply be interpreted as a demonstration that alpidem lacks anticontlict activity, as in another experimental proce-
Table 2 Effect of alpidem, diazepam, and chlordiazepoxide on shock-induced suppression of drinking in thirsty rats Treatment
Dose (mg/kg)
Anxiolytic properties ofalpidem In different animal models conventionally used to predict a compound's anxiolytic potential, alpidem displayed an overall profile which was substantially different from that of benzodiazepines such as chlordiazepoxide and diazepam. As summarized in Table I, alpidem increased food intake of mice placed in a novel environment and inhibited marble-burying behavior, as did the benzodiazepines. The compound was also active in antagonizing shock-induced suppression of Y-maze exploration. In these tests, performed on mice, alpidem showed a potency similar to that of chlordiazepoxide. However, in contrast to benzodiazepines, alpidem failed to antagonize shock-induced fighting in mice and lacked activity in the four-plate test.
Vehicle Alpidem
Diazepam Chlordiazepoxide
30 60 100 3 30
Route of administration i.p. p.o. shocks/3 min. 5.1 ±0.8 12.4±3.2" 13.1 ±2.3"
6.9±2.4 11.4±4.8 21.9±6.3'
21.8±4.2" 2O.7±6.0'
, p < 0.05; ., P < 0.01 vs vehicle-treated rats The test was carried out according to Vage/et al. (1971). Rats were deprived of water for 24 hours before the experiment. Drugs were administered 30 min. (i.p.) or 1 hour (p.o.) before placing the animals into an experimental chamber equipped with a metal drinking spout connected to an Omnitech anxiometer. Mild shocks (0.3 mAl were delivered through the spout every 20th lick. The data show the mean ± S.E.M. of number of shocks received during the three-minute test session.
Downloaded by: University of Iowa Libraries. Copyrighted material.
Model
Pharmacopsychiatry 23 (1990)
B. Zivkovic, E. Morel. D. Joly et al.
100
c
75
.. Alpidem
o Diazepam
Q
~
~
" "
c
Pharmacological and Behavioral Proriie of Alpidem as an Anxiolytic B. Zivkovic. E. Morel, D. Joly, Gh. Perrault, D. J. Sanger. K. G. Lloyd Synthelabo Recherche (L.E.R.S.), Bagneux, France
Pharmacological and behavioral studies in mice and rats have shown that the imidazopyridine alpidem possesses anxiolytic activity with a profile which is substantially different from that of benzodiazepines. Thus, in mice, alpidem inhibited marble-burying behavior and enhanced feeding under stressful conditions, as did benzodiazepines; in contrast to these drugs, however, alpidem was inactive against shock-induced fighting and shock-suppressed exploration. In rats, alpidem exerted anticonflict activity in the punished drinking test, but failed to antagonize punishmentinduced inhibition of operant behavior. Moreover, in rats trained to discriminate chlordiazepoxide from saline, alpidem did not produce a benzodiazepine-like interoceptive stimulus. Alpidem also produced anticonvulsant effects in a variety of tests sensitive to benzodiazepines. However, the order of potencies against convulsions induced by different convulsive agents was different from that of the benzodiazepines. Alpidem decreased motor performance in the rotarod test and only produced a deficit in muscle strength at doses which were more than 20 times higher than the doses active in anxiolytic tests. Moreover, alpidem did not interfere with the acquisition of conditioned fear, except at very high doses, indicating a weak potential to impair memory. The effects of alpidem were antagonized by f1umazenil, indicating that centtal omega receptors are involved in the action ofthis drug. The weak sedative effects of alpidem may be attributed to its low intrinsic activity, as demonstrated by its low efficacy in increasing latency to isoniazid-induced convulsions.
Pharmacopsychiatry 23 (1990) 108-113 (Supplement) © GeorgThieme Verlag Stuttgart· New York
Das pharmakologische und VerhaltensprofJJ von Alpidem als Anxiolytikum Pharmakologische und Verhaltensstudien bei Mäusen und Ratten haben gezeigt, daß das Imidazopyridin Alpidem eine anxiolytische Wirksamkeit mit einem Wirkungsprofil besitzt, das sich grundlegend von dem der Benzodiazepine unterscheidet. Bei Mäusen hemmte Alpidem beispielsweise den Trieb, Murmeln zu horten, und verstärkte das Freßverhalten bei Streßzuständen, was auch die Benzodiazepine taten, dagegen blieb Alpidem unwirksam gegenüber schockinduziertem Kampfverhalten und schockunterdfÜcktem Erforschungsdrang, im Gegensastz zu der Wirkung der Benzodiazepine. Bei Ratten übte Alpidem eine Antikonfliktwirkung beim bestraften Trinktest aus, bewirkte jedoch keinen antogonistischen Effekt gegen bestrafungsinduzierte Hemmung des Verhaltens gegenüber operanten Interventionen. Außerdem erzeugte Alpidem bei Ratten, die gelernt hatten zwischen Chlordiazepoxid und Kochsalzlösung zu unterscheiden, keinen benzodiazepinähnlichen interozeptiven Reiz. Alpidem erzeugte auch antikonvulsivischeWirkungen in einer Reihe von Tests, die gegen Benzodiadepine empfindlich waren. Die Rangfolge der Wirkungsstärke gegen Konvulsionen, die durch verschiedene Kunvulsiva ausgelöst wurden, utnerschied sich von derjenigen der Benzodiazepine. Alpidem setzte die motorische Bewegung beimRotastabtest herab und erzeugte ein Defizit der Muskelstärke erst bei Dosierungen, die um das 20fache über den anxiolytisch wirksamen Dosierungen lagen. Außerdem übte Alpidem bis zu sehr hohen Dosierungen keine WIrkung auf das Erlernen konditionierter Angst aus, was auf ein schwaches Potential hinsichtlich einer gedächtnishemmenden Wirkung hindeutet. Flumazenil zeigte einen Antagonismus gegen die Wirkungen von Alpidem, woraus geschlossen werden kann, daß der Wirkungsmechanismus von Alpidem mit zentralen Omegarezeptoren in Zusammenhang gebracht werden kann. Die schwach sedierende Wirkung des Alpidem kann auf seiner geringen Intrinsic Activity beruhen, wie sein niedriger Wirkungsgrad hinsichtlich einer Verlängerung der Latenz von isoniazidinduzierten Konvulsionen zeigt.
Downloaded by: University of Iowa Libraries. Copyrighted material.
Summary
Pharmacopsychiatry 23 (1990)
Pharmacological and Behavioral Profile 01Alpidem as an Anxiolytic
109
Table 1 Activity of alpidem, chlordiazepoxide, and diazepam in animal models of anxiolytic activity Minimum effective dose (mg/kg p.o.) Alpidem Chlordiazepoxide
Marble-burying in mice Stimulation of food intake - in mice - in rats Shock-induced fighting in mice Four-plate test in mice Y-maze in mice Staircase test in rats Punished leverpressing in rats
Diazepam
10
30
3
10 20 inactive up to 60 inactive 1 30 inactive up to 80 (ip)
10 20 10
3
Introduction Benzodiazepines are higWy effective in alleviating symptoms of different forms of anxious states, and for this reason these drugs are currently central to the therapy of anxiety. In addition to their anxiolytic action, benzodiazepines also exert anticonvulsant, myorelaxant, and sedative effects (Randa/l et al., 1974). All of these effects appear to be related to the same receptor mechanism and it is often difficult to determine the dose which would induce c1inically useful anxiolytic effects in the absence of other (e.g., myorelaxant or sedative) effects. As these latter effects may severe1y interrupt daily activities, there is c1early a need for anxiolytics devoid of these side-effects. Following the discovery of receptors involved in the action of benzodiazepines, serious efforts have been made to find compounds of a nonbenzodiazepine structure which would act through a similar mechanism (Williams, 1984). Among these new structures, some ofthe most promising compounds for c1inical use belong to the imidazo(l,2a)pyridine family which show high affinity for the omega receptor subtypes (Dimsdale et al., 1988), and ofwhich zolpidem (Stilnox(!l) has proved to be an effective hypnotic with numerous advantages over benzodiazepines (Nicholson and Pascoe, 1985; Monti, 1989). The present paper describes the neuropharmacological and behavioral effects of alpidem, another imidazo(I,2-a)pyridine which has been developed as an anx.iolytic agent.
3
10 3 30 3 (ip)
0.3 20 3 (ip)
Alpidem was also active in aseries of behavioral tests performed in rats. Here, for example, alpidem's potency in increasing food consumption in rats habituated to eating their total daily food requirements within four hours, was similar to that of chlordiazepoxide. Alpidem also decreased rearing activity, measured in an experimental chamber equipped with a staircase. While benzodiazepines produced a similar effect, low doses of these drugs, unlike alpidem, also increased exploratory activity. The biggest differences between alpidem and benzodiazepines, however, were observed in experimental procedures involving operant behavior. In punishment (contlict) procedures, in which rats are trained to press alever for food reward, benzodiazepines increase the rate of lever pressing during periods in which this behaviour is suppressed by electric shock punishment. This occurs at doses which have little effect on unpunished lever pressing (Cook and Davidson, 1973). Alpidem failed to produce any significant increase in the rate of lever pressing during punished periods, but when administered at relatively high doses it decreased the number of lever presses during the unpunished periods. These results cannot simply be interpreted as a demonstration that alpidem lacks anticontlict activity, as in another experimental proce-
Table 2 Effect of alpidem, diazepam, and chlordiazepoxide on shock-induced suppression of drinking in thirsty rats Treatment
Dose (mg/kg)
Anxiolytic properties ofalpidem In different animal models conventionally used to predict a compound's anxiolytic potential, alpidem displayed an overall profile which was substantially different from that of benzodiazepines such as chlordiazepoxide and diazepam. As summarized in Table I, alpidem increased food intake of mice placed in a novel environment and inhibited marble-burying behavior, as did the benzodiazepines. The compound was also active in antagonizing shock-induced suppression of Y-maze exploration. In these tests, performed on mice, alpidem showed a potency similar to that of chlordiazepoxide. However, in contrast to benzodiazepines, alpidem failed to antagonize shock-induced fighting in mice and lacked activity in the four-plate test.
Vehicle Alpidem
Diazepam Chlordiazepoxide
30 60 100 3 30
Route of administration i.p. p.o. shocks/3 min. 5.1 ±0.8 12.4±3.2" 13.1 ±2.3"
6.9±2.4 11.4±4.8 21.9±6.3'
21.8±4.2" 2O.7±6.0'
, p < 0.05; ., P < 0.01 vs vehicle-treated rats The test was carried out according to Vage/et al. (1971). Rats were deprived of water for 24 hours before the experiment. Drugs were administered 30 min. (i.p.) or 1 hour (p.o.) before placing the animals into an experimental chamber equipped with a metal drinking spout connected to an Omnitech anxiometer. Mild shocks (0.3 mAl were delivered through the spout every 20th lick. The data show the mean ± S.E.M. of number of shocks received during the three-minute test session.
Downloaded by: University of Iowa Libraries. Copyrighted material.
Model
Pharmacopsychiatry 23 (1990)
B. Zivkovic, E. Morel. D. Joly et al.
100
c
75
.. Alpidem
o Diazepam
Q
~
~
" "
c
