Comparative pharmacological activity of optical isomers of phenibut.
Phenibut (3-phenyl-4-aminobutyric acid) is a GABA (gamma-aminobutyric acid)-mimetic psychotropic drug which is clinically used in its racemic form. The aim of the present study was to compare the effects of racemic phenibut and its optical isomers in pharmacological tests and GABAB receptor binding studies. In pharmacological tests of locomotor activity, antidepressant and pain effects, S-phenibut was inactive in doses up to 500 mg/kg. In contrast, R-phenibut turned out to be two times more potent than racemic phenibut in most of the tests. In the forced swimming test, at a dose of 100 mg/kg only R-phenibut significantly decreased immobility time. Both R-phenibut and racemic phenibut showed analgesic activity in the tail-flick test with R-phenibut being slightly more active. An GABAB receptor-selective antagonist (3-aminopropyl)(diethoxymethyl)phosphinic acid (CGP35348) inhibited the antidepressant and antinociceptive effects of R-phenibut, as well as locomotor depressing activity of R-phenibut in open field test in vivo. The radioligand binding experiments using a selective GABAB receptor antagonist [3H]CGP54626 revealed that affinity constants for racemic phenibut, R-phenibut and reference GABA-mimetic baclofen were 177+/-2, 92+/-3, 6.0+/-1 microM, respectively. We conclude that the pharmacological activity of racemic phenibut relies on R-phenibut and this correlates to the binding affinity of enantiomers of phenibut to the GABAB receptor.
Dambrova
Maija
M
Latvian Institute of Organic Synthesis, Aizkraukles St. 21, Riga, LV-1006, Latvia. md@biomed.lu.lv <md@biomed.lu.lv>
Zvejniece
Liga
L
Liepinsh
Edgars
E
Cirule
Helena
H
Zharkova
Olga
O
Veinberg
Grigory
G
Kalvinsh
Ivars
I
D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D003220:Conflict, Psychological; D003863:Depression / Q000523:psychology; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D006358:Hot Temperature; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects; D053580:Muscle Strength / Q000187:drug effects; D009943:Organophosphorus Compounds / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects; D004856:Postural Balance / Q000187:drug effects; D011597:Psychomotor Performance / Q000187:drug effects; D011619:Psychotropic Drugs / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011930:Reaction Time / Q000187:drug effects; D018080:Receptors, GABA-B / Q000187:drug effects; D013237:Stereoisomerism; D013550:Swimming / Q000523:psychology; D005680:gamma-Aminobutyric Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
D000700:Analgesics; D000928:Antidepressive Agents; D018755:GABA Agonists; D018756:GABA Antagonists; D009943:Organophosphorus Compounds; D011619:Psychotropic Drugs; D018080:Receptors, GABA-B; C107353:CGP 54626; D005680:gamma-Aminobutyric Acid; C066430:CGP 35348; C008842:4-amino-3-phenylbutyric acid