Suppressing aggressive behavior with analogs of allopregnanolone (epalon)

Slavı́ková, Barbora; Kasal, Alexander; Uhlı́řová, Leona; Kršiak, M; Chodounská, Hana; Kohout, Ladislav

doi:10.1016/s0039-128x(00)00215-4

Cited by 13 publications

(16 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In some studies the antiaggressive effect of atypical neuroleptics was not accompanied by the decrease of locomotion [Aguilar et al, 1994;Redolat et al, 1991]. Next, the benzodiazepine receptor partial agonist Ro 19-8022 was found to have anxiolytic-like and potent antiaggressive effects without causing muscle relaxation or ataxia [Podhorna and Krsiak, 2000] and a pattern of increased aggression after low doses and decreased after high doses can be seen after neurosteroides administration [Miczek et al, 2003;Slavikova et al, 2001]. The selective decrease of aggression was also observed after the treatment of nicotinic agonists lobeline [Redolat et al, 2002] and delta9-tetrahydrocannabinol [Miczek, 1978].…”

Section: Discussionmentioning

confidence: 99%

Selective antiaggressive effect of an alpha‐2 adrenoceptor agonist naphthylmedetomidine in mice

Votava

Hess

Kršiak

2008

Aggressive Behavior

Self Cite

View full text Add to dashboard Cite

Alpha-2 adrenoceptors (alpha(2)-ARs) are critically involved in regulating neurotransmitter release from sympathetic nerves and neurons and play an important role in the regulation of awareness, arousal and vigilance. In our recent study, dexmedetomidine, a full alpha(2)-AR agonist, produced antiaggressive effects in the social conflict test in mice at doses that were twice smaller than those producing sedation. The aim of this study was to ascertain antiaggressive effect of a novel drug naphthylmedetomidine, with a more selective alpha(2)-AR activity. Behavioral effects of naphthylmedetomidine (150-1200 microg/kg i.p.) were studied in the activity cage and in the social conflict tests in mice. Naphthylmedetomidine dose dependently decreased aggressive behavior during social conflict in aggressive mice with significant reduction already at the lowest doses tested (150 microg/kg), whereas locomotion and social investigation were significantly decreased only after four times bigger dose of naphthylmedetomidine (600 microg/kg) in aggressive mice. Naphthylmedetomidine had no effect on aggression in nonaggressive mice. Naphthylmedetomidine reduced locomotion in the activity cage significantly only at the highest doses tested (600 and 1200 microg/kg), and this effect was only partially reversed by administration of high doses of an alpha-2 antagonist atipamezole (3 and 10 mg/kg). In nonaggressive mice, the difference between the dose reducing dominant social behavior (social investigation) and locomotion (150 and 300 microg/kg, respectively) was smaller than in aggressive mice. In conclusion, naphthylmedetomidine showed a very strong and selective antiaggressive effect in aggressive mice, which was devoid of locomotion-inhibiting/sedative effect. This study suggests that naphthylmedetomidine may have clinical potential as antiaggressive drug.

show abstract

Section: Discussionmentioning

confidence: 99%

Selective antiaggressive effect of an alpha‐2 adrenoceptor agonist naphthylmedetomidine in mice

Votava

Hess

Kršiak

2008

Aggressive Behavior

Self Cite

View full text Add to dashboard Cite

show abstract

“…In line with the above studies, Covey and coworkers prepared and evaluated a series of 13,24-cyclo-18,21-dinorcholanes containing a ketone or a conjugated ketone group at C-20, C-22, C-23 or C-24 (30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45) [28]. These ana- logues with conformationally constrained side chains were used to gain new information concerning the optimal location(s) for a hydrogen bond accepting group on the D-ring.…”

Section: Modifications At the D Ring And The Side Chainmentioning

confidence: 95%

“…Kasal and coworkers prepared the 3 -fluoro analogues (194 and 198) of allopregnanolone (1) and pregnanolone (2) respectively, taking into account that the strength of the C-F bond yielded products with a high metabolic stability [41,42]. Although the results of binding assays in vitro (using [ 3 H]muscimol and [ 35 S]TBPS) showed that the replacement of the 3 -hydroxyl by a 3 -fluoro gave a small loss in activity, compound 194 showed stronger antiaggressive effects than allopregnanolone (1) in a behavioral test with mice [42].…”

Section: The Data Inmentioning

confidence: 99%

Structure-Activity Relationships of Neuroactive Steroids Acting on the GABAA Receptor

Veleiro

Burton²

2009

CMC

View full text Add to dashboard Cite

The term "neuroactive steroid" (NAS) refers to steroids which, independent of their origin, are capable of modifying neural activities. These steroids positively or negatively modulate the function of members of the ligand-gated ion channel superfamily. Those with positive allosteric actions on the gamma-amino butyric acid type A receptor (GABAA receptor) have been shown to be potent anticonvulsants, anxiolytics, and antistress agents and to possess sedative, hypnotic, and anesthetic activities. New types of neuroactive steroids have been widely sought and structural modifications of the naturally occurring metabolites allopregnanolone, pregnanolone and allotetrahydrodeoxycorticosterone, have been examined in the light of the vast family of GABA receptor subtypes within the brain. Here we review the structure-activity relationship (SAR) of neuroactive steroid analogues obtained by modification of the steroid nucleus, including substitutions at the A, B, C, and D rings and the side chain, with emphasis on the different pharmacophores proposed.

show abstract

“…8,9 Neurosteroids, such as 3R-hydroxy-5R-pregnan-20-one (allopregnanolone, 1), 3R-hydroxy-5 -pregnan-20-one (pregnanolone, 2), and their 21-hydroxy derivatives, that is, 3R,21-dihydroxy-5R-pregnan-20-one (allotetrahydrodeoxycorticosterone, 3) and 3R,21-dihydroxy-5 -pregnan-20-one (tetrahydrodeoxycorticosterone, 4), have been proven to be anticonvulsant, anesthetic, antidepressant, and neuroprotectant agents. [10][11][12][13][14][15][16][17][18] In vitro assays reflect this positive modulation by showing an increase of both the Cl -influx through the GABA A receptor and the binding of GABA agonists or benzodiazepines. 8,14,15,[19][20][21][22][23] Although acting at higher concentrations than benzodiazepines and barbiturates, neurosteroids are valued 24 because they combine the effects of both and have fewer and less severe side effects.…”

Section: Introductionmentioning

confidence: 99%

Activity of B-Nor Analogues of Neurosteroids on the GABA_A Receptor in Primary Neuronal Cultures

et al. 2006

Self Cite

View full text Add to dashboard Cite

A GABA(A) receptor study of several B-nor analogues of allopregnanolone and pregnanolone has been carried out. B-norallopregnanolone (i.e., 3alpha-hydroxy-7-nor-5alpha-pregnan-20-one) was found comparable to allopregnanolone when measured with labeled TBPS. Analogous results were obtained from their effect on neurons in culture: this time, both 3alpha-hydroxy-7-nor-5xi-pregnan-20-ones (5 and 6) were found to stimulate [3H]flunitrazepam binding and GABA-induced 36Cl- influx. These effects were inhibited by GABA(A) receptor antagonists. Other analogues carrying electronegative substituents (epoxides 9 and 10 and ketone 12) in the B ring were inactive. Similarly, B-normal ketones 17, and 18 and 6-azasteroids 20 and 21 were also inactive. B-Nor analogues 5 and 6 did not induce neurotoxicity at relevant concentrations. A computational analysis of active and inactive neurosteroid analogues allowed the proposal of a 3D pharmacophoric hypothesis of their interaction with the GABA(A) receptor.

show abstract

Suppressing aggressive behavior with analogs of allopregnanolone (epalon)

Cited by 13 publications

References 21 publications

Selective antiaggressive effect of an alpha‐2 adrenoceptor agonist naphthylmedetomidine in mice

Selective antiaggressive effect of an alpha‐2 adrenoceptor agonist naphthylmedetomidine in mice

Structure-Activity Relationships of Neuroactive Steroids Acting on the GABAA Receptor

Activity of B-Nor Analogues of Neurosteroids on the GABA_A Receptor in Primary Neuronal Cultures

Contact Info

Product

Resources

About

Suppressing aggressive behavior with analogs of allopregnanolone (epalon)

Cited by 13 publications

References 21 publications

Selective antiaggressive effect of an alpha‐2 adrenoceptor agonist naphthylmedetomidine in mice

Selective antiaggressive effect of an alpha‐2 adrenoceptor agonist naphthylmedetomidine in mice

Structure-Activity Relationships of Neuroactive Steroids Acting on the GABAA Receptor

Activity of B-Nor Analogues of Neurosteroids on the GABAA Receptor in Primary Neuronal Cultures

Contact Info

Product

Resources

About

Activity of B-Nor Analogues of Neurosteroids on the GABA_A Receptor in Primary Neuronal Cultures