SB-656104-A: A novel 5-HT7 receptor antagonist with improved In vivo properties

Forbes, Ian J.; Douglas, Sara E.; Gribble, Andrew D.; Ife, Robert J.; Lightfoot, Andrew P.; Garner, Ashley E.; Riley, Graham J.; Jeffrey, Philip D.; Stevens, Alexander J.; Stean, Tania O.; Thomas, David R.

doi:10.1016/s0960-894x(02)00690-x

Cited by 69 publications

(76 citation statements)

References 10 publications

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“…On the other hand, an immunohistochemical study reported expression of 5-HT 7 receptors in the periventricular area of the PVN of developing rat brains (Muneoka and Takigawa, 2003), whereas a 5-HT 7 receptor-directed antisense oligonucleotide had no effect on baseline CORT levels in rats (Clemett et al, 1998). The present work notwithstanding is the first to show a functional role of 5-HT 7 receptors in stress-induced HPA axis activation, as demonstrated by the ability of the selective 5-HT 7 receptor antagonist, SB-656104 (Forbes et al, 2002), to inhibit significantly restraint-induced ACTH and CORT secretion in CTRL rats. Since magnified restraint-induced CORT responses in CRS animals were restored to CTRL values by SB-656104, they are most likely accounted for increased function and/or expression of 5-HT 7 receptors in the HPA axis.…”

Section: Discussionmentioning

confidence: 54%

“…Regarding the antagonist dose employed (1 mg/kg), this is half of the ED 50 oral dose of 2 mg/kg previously determined to antagonize 5-CT-induced hypothermia in guinea pigs with maximal inhibition achieved 2 hours after administration (Forbes et al, 2002). The reason for selecting this lower dose was to prevent potential interactions of SB-656104 with other 5-HT receptor mechanisms as the compound exhibits 12-, 31-, 45- and 91-fold higher affinity for 5-HT 7 receptors (pKi = 8.7) with respect to 5-HT 1D (pKi = 7.6), 5-HT 2A (pKi = 7.2), 5-HT 2B (pKi = 7.04), and 5-HT 5A receptors (pKi = 6.74), respectively (Forbes et al, 2002). Since the time gap after administration (i.e.…”

Section: Discussionmentioning

confidence: 99%

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Sensitization of restraint-induced corticosterone secretion after chronic restraint in rats: Involvement of 5-HT7 receptors

et al. 2013

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Serotonin (5-HT) modulates the hypothalamic-pituitary-adrenal (HPA) axis response to stress. We examined the effect of chronic restraint stress (CRS; 20 min/day) as compared to control (CTRL) conditions for 14 days, on: 1) restraint-induced ACTH and corticosterone (CORT) secretion in rats pretreated with vehicle or SB-656104 (a 5-HT7 receptor antagonist); 2) 5-HT7 receptor-like immunoreactivity (5-HT7-LI) and protein in the hypothalamic paraventricular nucleus (PVN) and adrenal glands (AG); 3) baseline levels of 5-HT and 5-hydroxyindolacetic acid (5-HIAA), and 5-HIAA/5-HT ratio in PVN and AG; and 4) 5-HT-like immunoreactivity (5-HT-LI) in AG and tryptophan hydroxylase (TPH) protein in PVN and AG. On day 15, animals were subdivided into Treatment and No treatment groups. Treatment animals received an i.p. injection of vehicle or SB-656104; No Treatment animals received no injection. Sixty min later, Treatment animals were either decapitated with no further stress (0 min) or submitted to acute restraint (10, 30, 60 or 120 min); hormone serum levels were measured. No Treatment animals were employed for the rest of measurements. CRS decreased body weight gain and increased adrenal weight. In CTRL animals, acute restraint increased ACTH and CORT secretion in a time of restraint-dependent manner; both responses were inhibited by SB-656104. Exposure to CRS abolished ACTH but magnified CORT responses to restraint as compared to CTRL conditions; SB-656104 had no effect on ACTH levels but significantly inhibited sensitized CORT responses. In CTRL animals, 5-HT7-LI was detected in magnocellular and parvocellular subdivisions of PVN and sparsely in adrenal cortex. Exposure to CRS decreased 5-HT7-LI and protein in the PVN, but increased 5-HT7-LI in the adrenal cortex and protein in whole AG. Higher 5-HT and 5-HIAA levels were detected in PVN and AG from CRS animals but 5-HIAA/5-HT ratio increased in AG only. Finally, whereas 5-HT-LI was sparsely observed in the adrenal cortex of CTRL animals, it strongly increased in the adrenal cortex of CRS animals. No TPH protein was detected in AG from both animal groups. Results suggest that CRS promotes endocrine disruption involving decreased ACTH and sensitized CORT responses to acute restraint. This phenomenon may be associated with increased function and expression of 5-HT7 receptors as well as 5-HT turnover in AG.

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Section: Discussionmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 99%

Sensitization of restraint-induced corticosterone secretion after chronic restraint in rats: Involvement of 5-HT7 receptors

et al. 2013

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“…Years later, GlaxoSmithKline reported on the identification of the antagonist 3 (SB-656104) (Chart 1), which showed an improved pharmacokinetic profile but displayed modest selectivity over 5-HT 2A , 5-HT 2B , and 5-HT 1D receptors. 22 The considerable amount of data on antagonists has allowed the generation of two receptorbased pharmacophores: the first containing features necessary for high 5-HT 7 receptor affinity and the other defining selectivity for this receptor subtype. 23 Considering the 5-HT 7 receptor agonists, a pharmacophore model has been generated from a set of 20 nonselective agonists.…”

Section: Introductionmentioning

confidence: 99%

Structural Modifications of N-(1,2,3,4-Tetrahydronaphthalen-1-yl)-4-Aryl-1-piperazinehexanamides: Influence on Lipophilicity and 5-HT₇ Receptor Activity. Part III

et al. 2008

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Starting from the previously reported 5-HT 7 receptor agents 4-7 with N-(1,2,3,4-tetrahydronaphthalen-1-yl)-4-aryl-1-piperazinehexanamide structure, the 1-(2-methylthiophenyl)-, 1-(2-diphenyl)-, 1-(2-isopropylphenyl)-, and 1-(2-methoxyphenyl)piperazine derivatives 8-31 were designed with the primary aim to obtain new compounds endowed with suitable physicochemical properties for rapid and extensive penetration into the brain. The affinities for 5-HT 7, 5-HT 1A, and D 2 receptors of compounds 8-31 were assessed, and several compounds displayed 5-HT 7 receptor affinities in the nanomolar range. Among these, N-(4-cyanophenylmethyl)-4-(2-diphenyl)-1-piperazinehexanamide (25) showed high 5-HT 7 receptor affinity (Ki = 0.58 nM), high selectivity over 5-HT 1A and D 2 receptors (324- and 245-fold, respectively), and agonist properties (maximal effect = 82%, EC 50 = 0.60 microM). After intraperitoneal injection in mice, 25 rapidly reached the systemic circulation and entered the brain. Its brain concentration-time profile paralleled that in plasma, indicating that 25 rapidly and freely distributes across the blood-brain barrier. Compound 25 underwent N-dealkylation to the corresponding 1-arylpiperazine metabolite.

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“…After washings, Lanterns of all chemsets were pooled together and treated with 1 M solution of TBAF in Tetrahydrofuran (THF) for 12 h, to provide support-bound free alcohol derivatives 6. Before the library synthesis, several conditions were studied to optimize the activation of a hydroxyl group (i.e., triflic anhydride [17], triphenylphosphine, and carbon tetrabromide [18]). The optimal conditions were found while using a methanesulfonyl chloride in anhydrous pyridine.…”

Section: Resultsmentioning

confidence: 99%

Solid‐Phase Synthesis of Aryl‐Alkylamine Derivatives Using Protected Aminoalcohol Building Blocks on SynPhase^TM Lanterns

et al. 2007

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A series of aryl-alkylamine carboxamide and sulfonamide derivatives were synthesized on a BAL linker using SynPhase TM Lanterns. All the reaction steps were performed on a solid support. The key stage was on-resin substitution of TBDPSi-protected aminoalcohols with various amines, which circumvented the multistep solution-phase synthesis of alkylamine building blocks. The chemistry applied allows building up focused libraries targeted on CNS receptors.

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SB-656104-A: A novel 5-HT7 receptor antagonist with improved In vivo properties

Cited by 69 publications

References 10 publications

Sensitization of restraint-induced corticosterone secretion after chronic restraint in rats: Involvement of 5-HT7 receptors

Sensitization of restraint-induced corticosterone secretion after chronic restraint in rats: Involvement of 5-HT7 receptors

Structural Modifications of N-(1,2,3,4-Tetrahydronaphthalen-1-yl)-4-Aryl-1-piperazinehexanamides: Influence on Lipophilicity and 5-HT₇ Receptor Activity. Part III

Solid‐Phase Synthesis of Aryl‐Alkylamine Derivatives Using Protected Aminoalcohol Building Blocks on SynPhase^TM Lanterns

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SB-656104-A: A novel 5-HT7 receptor antagonist with improved In vivo properties

Cited by 69 publications

References 10 publications

Sensitization of restraint-induced corticosterone secretion after chronic restraint in rats: Involvement of 5-HT7 receptors

Sensitization of restraint-induced corticosterone secretion after chronic restraint in rats: Involvement of 5-HT7 receptors

Structural Modifications of N-(1,2,3,4-Tetrahydronaphthalen-1-yl)-4-Aryl-1-piperazinehexanamides: Influence on Lipophilicity and 5-HT7 Receptor Activity. Part III

Solid‐Phase Synthesis of Aryl‐Alkylamine Derivatives Using Protected Aminoalcohol Building Blocks on SynPhaseTM Lanterns

Contact Info

Product

Resources

About

Structural Modifications of N-(1,2,3,4-Tetrahydronaphthalen-1-yl)-4-Aryl-1-piperazinehexanamides: Influence on Lipophilicity and 5-HT₇ Receptor Activity. Part III

Solid‐Phase Synthesis of Aryl‐Alkylamine Derivatives Using Protected Aminoalcohol Building Blocks on SynPhase^TM Lanterns