CGS 12066B dimaleate

Effect of 5-HT(1B) receptor ligands on self-administration of ethanol in an operant procedure in rats.[Pubmed:10837852]

Pharmacol Biochem Behav. 2000 May;66(1):129-36.

Recent evidence suggests that 5-HT(1B) receptor activation modifies ethanol's reinforcing, intoxicating and discriminative stimulus effects. The present study further explored the role played by 5-HT(1A/1B) receptors by examining their influence on oral ethanol self-administration. Male Wistar rats were trained on an FR 4 schedule to obtain a reinforcer of 0.1 12% w/v ethanol solution. Once responding was stable, the effect of the 5-HT(1A/1B) agonist RU24969 alone and in combination with the 5-HT(1B) antagonist GR127935 or the 5-HT(1A) antagonists (+) WAY100135 and (+) WAY100635 was assessed. The effect of RU24969 on ethanol's pharmacokinetic profile and on operant oral saline self-administration was also examined to assess if alterations in oral ethanol self-administration were due to nonspecific effects on level pressing. For comparison, we examined the effect of another 5-HT(1A/1B) agonist, CGS12066B, on oral ethanol self-administration. Both RU24969 (0.1 to 1 mg/kg) and CGS12066B (0.1 to 1 mg/kg) significantly suppressed oral ethanol self-administration. Administration of GR127935 (1 mg/kg), significantly reversed the effects elicited by RU24969, whereas neither WAY100635 (1 mg/kg) nor (+)WAY100135 (1 mg/kg) had any effect. The effects of lower doses of RU24969 on oral ethanol self-administration were selective as oral saline self-administration and blood ethanol levels were not altered by these doses. These data demonstrate that 5-HT(1B) receptor activation suppresses oral ethanol self-administration. These studies provide further evidence that 5-HT(1B) receptors play a modulatory role in ethanol's behavioral effects.

Interaction of arylpiperazines with 5-HT1A, 5-HT1B, 5-HT1C and 5-HT1D receptors: do discriminatory 5-HT1B receptor ligands exist?[Pubmed:2770889]

Naunyn Schmiedebergs Arch Pharmacol. 1989 Jun;339(6):675-83.

The effects of several putative 5-HT1 receptor-subtype selective ligands were investigated in biochemical models for 5-HT1A, 5-HT1B, and 5-HT1D receptors (inhibition of forskolin-stimulated adenylate cyclase activity in calf hippocampus, rat and calf substantia nigra, respectively) and 5-HT1C receptors (stimulation of inositol phosphates production in pig choroid plexus). Following compounds were studied: 5-HT (5-hydroxytryptamine), TFMPP (1-(m-trifluoromethylphenyl)piperazine), mCPP (1-(m-chlorophenyl)piperazine), CGS 12066 (7-trifluoromethyl-4-(4-methyl-1-piperazinyl)-pyrrolo[1,2-a] quinoxaline 1), isamoltane (CGP 361A, 1-(2-(1-pyrrolyl)-phenoxy)-3-isopropylamino-2-propranol), quipazine, 1-NP (1-(1-naphthyl)piperazine), and PAPP (LY165163, 1-[2-(4-aminophenyl)ethyl]-4-(3-trifluoromethylphenyl)- piperazine). Among reported 5-HT1B receptor selective drugs, TFMPP had similar potency at 5-HT1A, 5-HT1B and 5-HT1C receptors, mCPP did not separate between 5-HT1B and 5-HT1C receptors, CGS 12066 was equipotent at 5-HT1B and 5-HT1D receptors, and isamoltane was only slightly 5-HT1B versus 5-HT1A selective. Quipazine showed equal potency at 5-HT1B and 5-HT1C receptors and 1-NP did not discriminate between the four receptor subtypes. PAPP described as 5-HT1A receptor selective, was equally potent at 5-HT1A and 5-HT1D receptors. The potencies determined in second messenger studies were in good agreement with the affinity values determined in radioligand binding studies. Thus 5-HT1A, 5-HT1B, 5-HT1C and 5-HT1D receptors have different pharmacological profiles as predicted from radioligand binding studies. Despite claims to the contrary, none of the tested compounds had actual selectivity for a given 5-HT1 receptor subtype.(ABSTRACT TRUNCATED AT 250 WORDS)

Biochemical and pharmacological characterization of CGS 12066B, a selective serotonin-1B agonist.[Pubmed:3496228]

Eur J Pharmacol. 1987 Apr 7;136(1):1-9.

CGS 12066B is a novel pyrroloquinoxaline with selectivity for the serotonin-1B (5HT1B) recognition site as assessed by binding, biochemical and electrophysiological studies. The compound had an IC50 value of 51 nM at the 5HT1B recognition site as determined using the binding of [3H]5HT in the presence of 1 microM spiperone. At the 5HT1A receptor the compound had an IC50 value of 876 nM, providing a 5HT1A/5HT1B ratio of 17 in contrast to the putative 5HT1B selective agent trifluoromethylphenylpiperazine (TFMPP) which had a corresponding ratio of 3.6. The compound had minimal affinity for alpha 1-, alpha 2- and beta-adrenoceptors and for dopamine D-1 and D-2 receptors. CGS 12066B, in contrast to TFMPP, which was inactive, was found to inhibit dorsal raphe cell firing with an ED50 value of 358 nmol/kg i.v. The corresponding values for the 5HT1A selective agonists 8-OH-DPAT and ipsapirone were 1.3 and 33 nmol/kg. CGS 12066B was also effective in decreasing rat brain 5-HTP concentrations and inhibiting in vitro 5HT release. The data obtained indicate that CGS 12066B is a reasonably active 5HT1B site agonist, which due to its selectivity as compared to compounds such as TFMPP, will be a useful tool for evaluating the physiological role of such receptors in the mammalian CNS.