Biochemical and pharmacological characterization of CGS 12066B, a selective serotonin-1B agonist

Neale, Robert; Fallon, Scott; Boyar, William C.; Wasley, Jan W. F.; Martin, Louis L.; Stone, George; Glaeser, Bruce S.; Sinton, Christopher M.; Williams, Michael

doi:10.1016/0014-2999(87)90772-2

Cited by 158 publications

(66 citation statements)

References 31 publications

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“…This agent is a non- selective 5-HT receptor antagonist and acts even as an agonist (28,29). For example, methysergide acts as an antagonist on 5-HT 2A and 5-HT 2C serotonin receptors, but as an agonist on 5-HT 1A / 1B and 5-HT 1D serotonin receptors (30,31). With these findings taken into account, the present results suggest that 5-HT 1,2 serotonin receptors in the spinal dorsal horn do not play an important role in the analgesic action of Neurotropin.…”

Section: Discussionsupporting

confidence: 52%

Mechanisms of Analgesic Action of Neurotropin on Chronic Pain in Adjuvant-Induced Arthritic Rat: Roles of Descending Noradrenergic and Serotonergic Systems

et al. 2005

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Abstract. Neurotropin ® , a non-protein extract from the inflamed skin of rabbits inoculated with vaccinia virus, has been clinically used as an analgesic drug for treatment of chronic pain. In this study, we investigated the analgesic mechanisms of Neurotropin in the adjuvant-induced arthritic rat, a chronic pain model with inflammation. Neurotropin caused dose-dependent inhibition of hyperalgesia in the adjuvant-induced arthritic rat after single intravenous (10 -100 NU / kg) and oral (30 -200 NU / kg) administration. The analgesic effect of Neurotropin (intravenous 100 NU / kg and oral 200 NU/ kg) was significantly inhibited by intrathecal injections of the a 2 -adrenoceptor antagonist yohimbine (30 nmol / animal) and the selective 5-HT 3 serotonin receptor antagonist MDL72222 (30 nmol / animal), and slightly inhibited by the non-selective serotonin receptor antagonist methysergide (100 nmol / animal). The results suggest that the analgesic action of Neurotropin is at least in part due to the enhancement of noradrenergic and serotonergic descending pain inhibitory pathways. Neurotropin may be useful for the clinical management of chronic pain diseases such as a rheumatoid arthritis and osteoarthritis.

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Section: Discussionsupporting

confidence: 52%

Mechanisms of Analgesic Action of Neurotropin on Chronic Pain in Adjuvant-Induced Arthritic Rat: Roles of Descending Noradrenergic and Serotonergic Systems

et al. 2005

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“…Figure 1c shows that 6 mM NMDA and 50 mM CGS 12066A (a selective agonist for 5-HT 1B/D receptors (Neale et al 1987)) induced a regular alternating pattern (period 2.0 AE 0.2 s) slower than the one observed with NMDA alone (¢gure 1a). Data pooled from six preparations are represented in the fourth bar of the histogram of ¢gure 1e and show that the cycle period was signi¢cantly (p50.001) larger (153 AE20%) than the control one.…”

Section: Resultsmentioning

confidence: 99%

Serotonin-induced inhibition of locomotor rhythm of the rat isolated spinal cord is mediated by the 5–HT1 receptor class

Beato

Nistri

1998

Proc. R. Soc. Lond. B

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The neurotransmitter serotonin (5-HT) induces rhythmic motor patterns (¢ctive locomotion) of the neonatal rat spinal cord in vitro; this is a useful experimental model to study the generation of a motor programme at exclusively spinal level. Nevertheless, 5-HT slows down the ¢ctive locomotion typically elicited by activation of NMDA glutamate receptors, suggesting a complex action of this monoamine. By means of electrophysiological recordings from multiple ventral roots we demonstrated that the decrease caused by 5-HT in NMDA-induced periodicity was dose-dependent, enhanced after pharmacological blocking of 5-HT 2 excitatory receptors, and imitated by pharmacological agonists of the 5-HT 1 receptor family. Selective blockers of the 5-HT 1A or 5-HT 1B/D receptor classes, either alone or in combination, largely (but not completely) attenuated this inhibitory action of 5-HT. It is concluded that the principal inhibitory action of 5-HT on the spinal locomotor network was mediated by certain subtypes of the 5-HT 1 receptor class, which tends to oppose the 5-HT 2 receptor-mediated excitation of the same network.

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“…Pyrrolo[1,2-a]quinoxalines and their 4,5-dihydro derivatives exhibit interesting biological and pharmacological properties [1][2][3][4][5][6]. Particularly the compounds 1 proved to be useful materials for pharmaceutical preparations [5]; the commercially available maleate of compound 2 (CGS 12066B) is recognized as a potent and selective serotonin-1B agonist [6].…”

mentioning

confidence: 99%

“…Particularly the compounds 1 proved to be useful materials for pharmaceutical preparations [5]; the commercially available maleate of compound 2 (CGS 12066B) is recognized as a potent and selective serotonin-1B agonist [6].…”

mentioning

confidence: 99%

A versatile synthesis of 4,5‐dihydropyrrolo[1,2‐a]quinoxalines

Abonı́a

Insuasty

Quiroga

et al. 2001

Journal of Heterocyclic Chem

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The reaction of 1-(2-aminophenyl)pyrrole with aromatic or heteroaromatic aldehydes in ethanol and catalytic amounts of acetic acid leads to 4,5-dihydropyrrolo[1,2-a]quinoxalines in high yields. When aliphatic aldehydes were used under the same conditions, a slow oxidation to the corresponding pyrrolo[1,2-a]quinoxalines can occur; the oxidation can be avoided by preparing in situ the 5-acetyl derivatives of the 4,5-dihydropyrrolo[1,2-a]quinoxalines.J. Heterocyclic Chem., 38, 671 (2001).Pyrrolo[1,2-a]quinoxalines and their 4,5-dihydro derivatives exhibit interesting biological and pharmacological properties [1][2][3][4][5][6]. Particularly the compounds 1 proved to be useful materials for pharmaceutical preparations [5]; the commercially available maleate of compound 2 (CGS 12066B) is recognized as a potent and selective serotonin-1B agonist [6].Although the obtention of 4,5-dihydropyrrolo[1,2-a]-quinoxalines from o-phenylenediamine and 2-hydroxy-1,5-diketones has been previously reported [8], 1-(2-aminophenyl)pyrrole (3) has been recognized as an excellent precursor for the preparation of these and related compounds [9][10][11]. However, the feasibility of the latter method is strongly dependent on the carbonyl compound and the reaction conditions. It has been reported for example that the hydrochloride of compound 3 in contrast to the free base does not react with benzaldehyde [10].The formation of 4,5-dihydropyrrolo[1,2-a]quinoxalines involves a Mannich type reaction for which a primary or secondary amine, an aldehyde (formaldehyde generally) and a nucleophilic carbon are necessary. Besides formaldehyde, other reactive aldehydes have been applied in this process, some of them unsuccessfully [12,13]. For that reason, we tried to explore the scope and the limitations of this reaction starting from 1-(2-aminophenyl)-pyrrole (3), which serves simultaneously as amine and nucleophilic carbon. When 3 and aldehydes 4a-i dissolved in ethanol were heated for 5 to 10 minutes at 50 °C in the presence of catalytic amount of acetic acid, the products 5a-i were generated in excellent yields. Terephthalaldehyde (4j) reacts with two equivalents of 3 to give 84% of 1,4-bis(4,5-dihydropyrrolo[1,2-a]quinoxalin-4-yl)benzene 5j. Carbon atom C-4 in 5 is a chiral center. Therefore 5a-i were obtained as racemates; however, compound 5j has two chiral centers and should be generated in the chiral form (RR and SS) and in the achiral meso form. Although the two chiral centers are relatively far apart, some of the 13 C nmr signals are doubled, which is a proof for diastereomers. The statistical ratio RR/SS: meso would be 1:1; however, the 13 C nmr spectrum of the raw product reveals that one component predominates strongly.When aliphatic aldehydes like 4k and 4l were applied, the products 5k and 5l showed a slow oxidation to the corresponding pyrrolo[1,2-a]quinoxalines. The oxidation could be avoided by the in situ subsequently performed acetylation with acetic anhydride; thus, the amides 6k and 6l were obtained.The mild reaction conditions ...

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Biochemical and pharmacological characterization of CGS 12066B, a selective serotonin-1B agonist

Cited by 158 publications

References 31 publications

Mechanisms of Analgesic Action of Neurotropin on Chronic Pain in Adjuvant-Induced Arthritic Rat: Roles of Descending Noradrenergic and Serotonergic Systems

Mechanisms of Analgesic Action of Neurotropin on Chronic Pain in Adjuvant-Induced Arthritic Rat: Roles of Descending Noradrenergic and Serotonergic Systems

Serotonin-induced inhibition of locomotor rhythm of the rat isolated spinal cord is mediated by the 5–HT1 receptor class

A versatile synthesis of 4,5‐dihydropyrrolo[1,2‐a]quinoxalines

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