The Selective 5-HT_1BReceptor Inverse Agonist 1‘-Methyl-5-[[2‘-methyl-4‘- (5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]carbonyl]-2,3,6,7-tetrahydro- spiro[furo[2,3-f]indole-3,4‘-piperidine] (SB-224289) Potently Blocks Terminal 5-HT Autoreceptor Function Both in Vitro and in Vivo

Abstract

5-HT1 receptors are members of the G-protein-coupled receptor superfamily and are negatively linked to adenylyl cyclase activity. The human 5-HT1B and 5-HT1D receptors (previously known as 5-HT1Dbeta and 5-HT1Dalpha, respectively), although encoded by two distinct genes, are structurally very similar. Pharmacologically, these two receptors have been differentiated using nonselective chemical tools such as ketanserin and ritanserin, but the absence of truly selective agents has meant that the precise function of the 5-HT1B and 5-HT1D receptors has not been defined. In this paper we describe how, using computational chemistry models as a guide, the nonselective 5-HT1B/5-HT1D receptor antagonist 4 was structurally modified to produce the selective 5-HT1B receptor inverse agonist 5, 1'-methyl-5-[[2'-methyl-4'-(5-methyl-1,2, 4-oxadiazol-3-yl)biphenyl-4-yl]carbonyl]-2,3,6, 7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (SB-224289). This compound is a potent antagonist of terminal 5-HT autoreceptor function both in vitro and in vivo.

Pharmacological Modulations of the Serotonergic System in a Cell-Model of Familial Alzheimer’s Disease

“…Only a single time point and concentration was used, however these were chosen based on previous reports. Although we did not observe the expected reduction of 5-HT after 5-HT1B antagonist treatments, in contrast to another study [43], this discrepancy could be attributed to different cell-line types used in the two different studies and remains to be resolved. Moreover, the lack of and additional control cell overexpressing the APP wild type, without the APPswe mutation, is another limitation of this study.…”

“…MAO-Glo TM kit for measuring MAOA enzyme activity was purchased from Promega, USA. The primary antibodies for the p70S6, phospho-p70S6 (Thr389), phospho-p70S6-(Thr421, Ser424), p70S6 and pMAPK (42)(43)(44), total MAPK and ␤-Actin were purchased from Cell signaling, USA. Taqman gene expression assay for the human 5-HT1B-receptor, SERT, MAOA, p11, RPLP0 and GAPDH were purchased from Thermo Fisher Scientific, USA.…”

Local potentiation of excitatory synapses by serotonin and its alteration in rodent models of depression

“…Administration of fluoxetine via the drinking water restored a high level of sucrose preference to SDS animals after 1 week. Administration of the 5-HT 1B R antagonist SB224289 (4 mg/l) 40 had no effect on the high sucrose preference of naïve mice, but prevented the increase in sucrose preference produced by chronic fluoxetine administration in mice that had lost their sucrose preference after SDS. Similarly, naïve 5-HT 1B R −/− mice had a high sucrose preference 41 that was lost after 3–5 weeks of CUS (Fig.…”

Pharmacological diversity between native human 5‐HT1B and 5‐HT1D receptors sited on different neurons and involved in different functions

“…SB‐224289, a recently proposed selective h5‐HT 1B receptor ligand ( Roberts et al ., 1997 ; Gaster et al ., 1998 ), abolished the effect of 5‐HT when present in the superfusion medium at 1 μ M . At this concentration, SB‐224289 did not modify, on its own, the basal (not shown) or the K + ‐evoked release of tritium (Figure 1).…”

“…In binding studies on receptors expressed in CHO cells SB‐216641 and SB‐224289 had, respectively, 25 and 80 fold higher affinity for h5‐HT 1B than h5‐HT 1D receptors; conversely, BRL‐15572 had 60 fold higher affinity for h5‐HT 1D than h5‐HT 1B receptors. In functional assays ([ 35 S]‐GTPγS binding and cyclic AMP accumulation) with the above cloned receptor expression system, SB‐216641 and BRL‐15572 displayed agonist intrinsic activity at both h5‐HT 1B and h5‐HT 1D receptors ( Price et al ., 1997 ), whereas SB‐224289 behaved as an inverse agonist ( Gaster et al ., 1998 ).…”