Microwave-enhanced synthesis of 2,3,6-trisubstituted pyridazines: application to four-step synthesis of gabazine (SR-95531)

2010 ◽  
Vol 8 (18) ◽  
pp. 4131 ◽  
Author(s):  
Navnath Gavande ◽  
Graham A. R. Johnston ◽  
Jane R. Hanrahan ◽  
Mary Chebib
Keyword(s):  
Sr 95531

BICUCULLINE/BACLOFEN-INSENSITIVE GABA RESPONSE IN CRUSTACEAN NEURONES IN CULTURE

1994 ◽  
Vol 191 (1) ◽  
pp. 167-193
Author(s):  
C Jackel ◽  
W Krenz ◽  
F Nagy
Keyword(s):  
Reversal Potential ◽  
Membrane Conductance ◽  
Gamma Aminobutyric Acid ◽  
Action Potential Firing ◽  
Patch Clamp Technique ◽  
Conformationally Restricted ◽  
Whole Cell Patch Clamp ◽  
Gabac Receptor ◽  
Potential Firing ◽  
Sr 95531

Neurones were dissociated from thoracic ganglia of embryonic and adult lobsters and kept in primary culture. When gamma-aminobutyric acid (GABA) was applied by pressure ejection, depolarizing or hyperpolarizing responses were produced, depending on the membrane potential. They were accompanied by an increase in membrane conductance. When they were present, action potential firing was inhibited. The pharmacological profile and ionic mechanism of GABA-evoked current were investigated under voltage-clamp with the whole-cell patch-clamp technique. The reversal potential of GABA-evoked current depended on the intracellular and extracellular Cl- concentration but not on extracellular Na+ and K+. Blockade of Ca2+ channels by Mn2+ was also without effect. The GABA-evoked current was mimicked by application of the GABAA agonists muscimol and isoguvacine with an order of potency muscimol>GABA>isoguvacine. cis-4-aminocrotonic acid (CACA), a folded and conformationally restricted GABA analogue, supposed to be diagnostic for the vertebrate GABAC receptor, also induced a bicuculline-resistant chloride current, although with a potency about 10 times lower than that of GABA. The GABA-evoked current was largely blocked by picrotoxin, but was insensitive to the GABAA antagonists bicuculline, bicuculline methiodide and SR 95531 at concentrations of up to 100 µmol l-1. Diazepam and phenobarbital did not exert modulatory effects. The GABAB antagonist phaclophen did not affect the GABA-induced current, while the GABAB agonists baclophen and 3-aminopropylphosphonic acid (3-APA) never evoked any response. Our results suggest that lobster thoracic neurones in culture express a chloride-conducting GABA-receptor channel which conforms to neither the GABAA nor the GABAB types of vertebrates but shows a pharmacology close to that of the novel GABAC receptor described in the vertebrate retina.

Contributions of GABAA receptors and GABAC receptors to acetylcholine release and directional selectivity in the rabbit retina

1997 ◽  
Vol 14 (5) ◽  
pp. 939-948 ◽  
Author(s):  
Stephen C. Massey ◽  
David M. Linn ◽  
Christopher A. Kittila ◽  
Wajid Mirza
Keyword(s):  
Ganglion Cells ◽  
Bipolar Cells ◽  
High Dose ◽  
Directional Selectivity ◽  
Ach Release ◽  
Gaba Antagonists ◽  
Inhibitory Neurotransmitter ◽  
Postsynaptic Receptors ◽  
Release Of Acetylcholine ◽  
Sr 95531

AbstractGABA is a major inhibitory neurotransmitter in the mammalian retina and it acts at many different sites via a variety of postsynaptic receptors. These include GABAA receptors and bicuculline-resistant GABAC receptors. The release of acetylcholine (ACh) is inhibited by GABA and strongly potentiated by GABA antagonists. In addition, GABA appears to mediate the null inhibition which is responsible for the mechanism of directional selectivity in certain ganglion cells. We have used these two well-known examples of GABA inhibition to compare three GABA antagonists and assess the contributions of GABAA and GABAC receptors. All three GABA antagonists stimulated ACh release by as much as ten-fold. By this measure, the ED50s for SR-95531, bicuculline, and picrotoxin were 0.8, 7.0, and 14 μM, respectively. Muscimol, a potent GABAA agonist, blocked the effects of SR-95531 and bicuculline, but not picrotoxin. This indicates that SR-95531 and bicuculline are competitive antagonists at the GABAA receptor, while picrotoxin blocks GABAA responses by acting at a different, nonreceptor site such as the chloride channel. In the presence of a saturating dose of SR-95531 to completely block GABAA receptors, picrotoxin caused a further increase in the release of ACh. This indicates that picrotoxin potentiates ACh release by a mechanism in addition to the block of GABAA responses, possibly by also blocking GABAC receptors, which have been associated with bipolar cells. All three GABA antagonists abolished directionally selective responses from ON/OFF directional-selective (DS) ganglion cells. In this system, the ED50s for SR-95531, bicuculline, and picrotoxin were 0.7 μM, 8 μM, and 94.6 μM, respectively. The results with SR-95531 and bicuculline indicate that GABAA receptors mediate the inhibition responsible for directional selectivity. The addition of picrotoxin to a high dose of SR-95531 caused no further increase in firing rate. The comparatively high dose required for picrotoxin also suggests that GABAC receptors do not contribute to directional selectivity. This in turn suggests that feedforward GABAA inhibition, as opposed to feedback at bipolar terminals, is responsible for the null inhibition underlying directional selectivity.

scholarly journals The influence of Rol5-1788, SR-95531 and Picrotoxin on food intake induced by benzodiazepines and CABAA agonists in rats

1997 ◽  
Vol 73 ◽  
pp. 173
Author(s):  
Yasushi Noguchi ◽  
Chika Murakami ◽  
Kunie Kamata ◽  
Hikio Nakamura
Keyword(s):  
Food Intake ◽  
Sr 95531

ChemInform Abstract: Microwave-Enhanced Synthesis of 2,3,6-Trisubstituted Pyridazines: Application to Four-Step Synthesis of Gabazine (SR-95531).

ChemInform ◽  
2010 ◽  
Vol 42 (4) ◽  
pp. no-no
Author(s):  
Navnath Gavande ◽  
Graham A. R. Johnston ◽  
Jane R. Hanrahan ◽  
Mary Chebib
Keyword(s):  
Sr 95531

Steroid inhibition of [3H]SR 95531 binding to the GABAA recognition site

1996 ◽  
Vol 304 (1-3) ◽  
pp. 141-146 ◽  
Author(s):  
Jon E. Hawkinson ◽  
Manuel Acosta-Burruel ◽  
Catherine L. Kimbrough ◽  
Dayan B. Goodnough ◽  
Paul L. Wood
Keyword(s):  
Recognition Site ◽  
Sr 95531

GABAA receptor binding and localization in the tiger salamander retina

2000 ◽  
Vol 17 (1) ◽  
pp. 11-21 ◽  
Author(s):  
HAO WANG ◽  
KELLY M. STANDIFER ◽  
DAVID M. SHERRY
Keyword(s):  
Gaba Receptors ◽  
Radioligand Binding ◽  
Specific Binding ◽  
Horizontal Cell ◽  
Tiger Salamander ◽  
Gamma Aminobutyric Acid ◽  
Binding Studies ◽  
Binding Properties ◽  
Gaba Binding ◽  
Sr 95531

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the retina and also appears to act as a trophic factor regulating photoreceptor development and regeneration. Although the tiger salamander is a major model system for the study of retinal circuitry and regeneration, our understanding of GABA receptors in this species is almost exclusively based on the results of physiological studies. Therefore, we have examined the pharmacological binding properties of GABAA receptors and their anatomical localization in the tiger salamander retina. Radioligand-binding studies showed that specific 3H-GABA binding to GABAA receptors was dominated by a single high-affinity binding site (Kd = 15.6 ± 6.9 nM). Specific binding of 3H-GABA was almost completely eliminated by muscimol (Ki = 105 ± 62 nM) and bicuculline (Ki = 14.3 ± 2.2 μM); however, SR-95531 only displaced about 40% of specific 3H-GABA binding (Ki = 35.0 ± 3.8 nM). These data indicate that there are at least two subtypes of GABAA receptors present in the salamander retina that can be distinguished by their antagonist binding properties: one sensitive to both bicuculline and SR-95531, and one sensitive to bicuculline but insensitive to SR-95531. Because localization of GABA receptors in the salamander retina by immunocytochemistry is problematic, GABAA receptors were localized by fluorescent ligand binding combined with immunocytochemical labeling for cell specific markers. Binding of fluorescently labeled muscimol to GABAA receptors was present in both plexiform layers and on photoreceptor cell bodies. GABAA receptors in the outer plexiform layer were localized to both photoreceptor terminals and horizontal cell processes.

scholarly journals Сравнение фармакологических эффектов гептапептида селанка при внутрибрюшинном и интраназальном введении мышам BALB/C и C57BL/6

2016 ◽  
Vol 79 (9) ◽  
pp. 3-11
Author(s):  
Екатерина В. Васильева ◽  
Е. А. Кондрахин ◽  
Р. М. Салимов ◽  
Г. И. Ковалёв
Keyword(s):  
Mk 801 ◽  
Sr 95531

С использованием теста «закрытый крестообразный лабиринт» проведено сравнение влияния при внутрибрюшинном (в/б) и интраназальном (и/н) введении гептапептида селанка (300 мкг/кг/день в течение 5 дней), обладающего анксиолитическим и ноотропным свойствами, на поведение мышей инбредных линий BALB/с и C57BL/6, а также на NMDA- и ГАМКA-рецепторы мозга. Показано, что эффективность селанка при обоих путях введения выявляется лишь у мышей линии BALB/c, исходно характеризующейся сниженной по сравнению с C57BL/6 исследовательской активностью, а также более высоким уровнем тревожности. У мышей линии BALB/c при в/б введении селанк увеличивал количество мест связывания [G-3H]SR 95531 с ГАМКA-рецепторами фронтальной коры мозга на 38 %, не изменяя характеристик связывания с NMDA-рецепторами гиппокампа. Напротив, при и/н введении селанк приводил к повышению плотности мест связывания [G-3H]MK-801 на 23 % при отсутствии влияния на ГАМКA-рецепторы. По-видимому, разница в спектрах фармакологического действия пептида при разных путях введения зависит от различий фармакокинетики вещества и динамики формирования анксиолитического и ноотропного эффектов препарата.

Синтез и цереброваскулярная противоишемическая активность новых производных 5-гидроксиадамантан-2-она

2018 ◽  
Vol 52 (2) ◽  
pp. 3-7
Author(s):  
Елена Владимировна Курза ◽  
Н. И. Авдюнина ◽  
Тамара Сергеевна Ганьшина ◽  
Д. В. Масленников ◽  
А. И. Турилова ◽  
...  
Keyword(s):  
Sr 95531

Проведен синтез и фармакологическое изучение новых производных 5-гидроксиадамантан-2-она с гетероароматическими, ароматическими и алифатическими кислотами (никотиновой, янтарной, пара-хлорфеноксиуксусной, 3,4,5-триметоксибензойной и анисовой) с целью поиска соединений, обладающих цереброваскулярной противоишемической активностью и не оказывающих гипотензивного действия. Наиболее выраженное влияние на мозговое кровообращение в условиях ишемии мозга оказывают эфиры янтарной кислоты 5-гидроксиадамантан-2-она (диэфир — Iа и моноэфир — Iб по 100 мг/кг внутривенно). Они не понижают уровень артериального давления, а моноэфир менее токсичен, LD50 740,0 (676,0 – 804,0) мг/кг. Анализ цереброваскулярного эффекта эфиров янтарной кислоты 5-гидроксиадамантан-2-она с помощью бикукуллина выявил участие ГАМК-ергического механизма сосудов мозга в его реализации. Однако методом радиолигандного анализа in vitro с использованием специфического лиганда [3H]-SR 95531 взаимодействие этих эфиров с ГАМКА-рецепторами мембран мозга крыс показано не было. Таким образом, моноэфир янтарной кислоты 5-гидроксиадамантан-2-она обладает выраженной цереброваскулярной противоишемической активностью и не оказывает гипотензивного эффекта. Последнее его выгодно отличает от используемых в неврологии препаратов (пикамилона, мексидола, нимодипина, циннаризина и кавинтона).

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