5-HT₇ Receptor ( pKi = 8.3 )
5-HT7 receptor (pKi = 8.3)

SB-269970 inhibits 5-CT-stimulated adenylyl cyclase activity in guinea-pig hippocampal membranes. The concentration-response curve of 5-CT shows a concentration-related rightward shift when SB-269970 (0.03 μM, 0.1 μM, 0.3 μM, and 1 μM) is used, but the maximal response to 5-CT is not significantly changed. When superfused alone, SB-269970 (1 μM) has no effect on 5-HT efflux.

---

SB-269970 exhibits high affinity for the 5-HT7 receptor with a pKi of 8.3. It functions as a potent antagonist, inhibiting 5-CT-stimulated adenylyl cyclase activity in guinea-pig hippocampal membranes and 5-HT7(a)/HEK293 membranes with pKB of 8.3 and pA2 of 8.5, respectively. The compound demonstrates remarkable selectivity, showing >50-fold selectivity over other serotonin receptor subtypes and >100-fold selectivity across a broad range of receptors and enzymes. When superfused alone at 1 μM, it has no effect on 5-HT efflux, confirming its specificity as an antagonist rather than a modulator of serotonin release. In binding assays using [³H]-SB-269970, the compound displays a KD of 1.0 nM, with association and dissociation rate constants (k+1 = 0.05 nM⁻¹min⁻¹, k−1 = 0.05 min⁻¹). Saturation binding reveals KD values of 1.25 nM for h5-HT7(a) and 1.7 nM for guinea-pig cortex. Functional antagonist activity is confirmed through inhibition of 5-CT-stimulated adenylyl cyclase, with the pA2 value of 8.5 calculated from the rightward shift of the 5-CT concentration-response curve without significant alteration of maximal response.

SB-269970 (3–30 mg/kg; intraperitoneal; once) dramatically inhibits the hyperactivity caused by amphetamine and ketamine[2].

---

In vivo, SB-269970 demonstrates significant pharmacological activity across multiple rodent models. At doses of 3–30 mg/kg administered intraperitoneally, it significantly attenuates amphetamine-induced hyperactivity and blocks ketamine-induced effects, suggesting potential antipsychotic-like properties. The compound also reverses amphetamine disruption of prepulse inhibition (PPI) at 30 mg/kg without enhancing PPI alone, indicating a specific modulatory effect on sensorimotor gating deficits. In addition, SB-269970 potentiates REM sleep suppression induced by citalopram in rats, supporting its role in modulating serotonergic transmission. The antidepressant effects of SB-269970 occur via changes in dorsal raphe activity and subsequent cortical serotonin release. In guinea-pigs, 5-CT-induced hypothermia is blocked by SB-269970 with an ED50 of 2.96 mg/kg i.p., confirming target engagement in vivo. The compound's ability to exert rapid-onset antidepressant effects either alone or in combination with lower doses of conventional antidepressants has been a key finding driving interest in the 5-HT7 receptor as a therapeutic target.

SB269970 an antagonist of the 5-HT7 receptor with pKi of 8.3, exhibits >50-fold selectivity against other receptors. The novel 5-HT(7) receptor antagonist, SB-269970-A, potently displaced [(3)H]-5-CT from human 5-HT(7(a)) (pK(i) 8.9+/-0.1) and 5-HT(7) receptors in guinea-pig cortex (pK(i) 8.3+/-0.2). 5-CT stimulated adenylyl cyclase activity in 5-HT(7(a))/HEK293 membranes (pEC(50) 7.5+/-0.1) and SB-269970-A (0.03 - 1 microM) inhibited the 5-CT concentration-response with no significant alteration in the maximal response. The pA(2) (8.5+/-0.2) for SB-269970-A agreed well with the pK(i) determined from [(3)H]-5-CT binding studies. 5-CT-stimulated adenylyl cyclase activity in guinea-pig hippocampal membranes (pEC(50) of 8.4+/-0.2) was inhibited by SB-269970-A (0.3 microM) with a pK(B) (8.3+/-0.1) in good agreement with its antagonist potency at the human cloned 5-HT(7(a)) receptor and its binding affinity at guinea-pig cortical membranes. 5-HT(7) receptor mRNA was highly expressed in human hypothalamus, amygdala, thalamus, hippocampus and testis. SB-269970-A was CNS penetrant (steady-state brain : blood ratio of ca. 0.83 : 1 in rats) but was rapidly cleared from the blood (CLb=ca. 140 ml min(-1) kg(-1))[1].

---

[³H]-SB-269970 binding assays are performed using membranes from h5-HT7(a)/HEK293 cells or guinea-pig cerebral cortex. Membranes are incubated with 1 nM [³H]-SB-269970 for 40 minutes at room temperature. Specific binding, which accounts for >90% of total binding, is defined using 10 µM methiothepin. Association and dissociation rate constants (k+1 = 0.05 nM⁻¹min⁻¹, k−1 = 0.05 min⁻¹) yield a KD of 1.0 nM. Saturation binding experiments reveal KD values of 1.25 nM for h5-HT7(a) and 1.7 nM for guinea-pig cortex. Selectivity profiling is conducted against a broad range of receptors and enzymes to confirm the compound's specificity for the 5-HT7 receptor.

1. The presence of 5-HT(7) receptor mRNA and protein in 5-HT neurons suggests that this receptor may act as a 5-HT autoreceptor. In this study, the effect of the 5-HT(7) receptor antagonist, SB-269970 ((R)-1-[3-hydroxy phenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl]pyrrolidine), was investigated on 5-HT release in the guinea-pig and rat cortex and the rat dorsal raphe nucleus (DRN), using the techniques of in vitro [(3)H]-5-HT release or fast cyclic voltammetry, respectively. 2. Cortical slices were loaded with [(3)H]-5-HT and release was evoked by electrical stimulation. 5-CT inhibited the evoked release of [(3)H]-5-HT in a concentration-dependent manner. SB-269970 had no significant effect on [(3)H]-5-HT release while the 5-HT(1B) receptor antagonist, SB-224289 significantly potentiated [(3)H]-5-HT release. In addition, SB-269970 was unable to attenuate the 5-CT-induced inhibition of release while SB-224289 produced a rightward shift of the 5-CT response, generating estimated pK(B) values of 7.8 and 7.6 at the guinea-pig and rat terminal 5-HT autoreceptors respectively. 3. Rat DRN slices were electrically stimulated and the evoked 5-HT efflux detected by voltammetric analysis. 8-OH-DPAT inhibited evoked 5-HT efflux and was fully reversed by WAY 100635. SB-269970 had no effect on either 5-HT efflux per se or 8-OH-DPAT-induced inhibition of 5-HT efflux. In addition, 5-CT inhibited 5-HT efflux in a concentration-dependent manner. SB-269970 was unable to attenuate the 5-CT-induced inhibition of 5-HT efflux. 4. In conclusion, we were unable to provide evidence to suggest a 5-HT autoreceptor role for 5-HT(7) receptors. However, investigations with more selective 5-HT(7) receptor agonists are needed to confirm the data reported here.[2]

---

The novel 5-HT(7) receptor antagonist, SB-269970-A, potently displaced [(3)H]-5-CT from human 5-HT(7(a)) (pK(i) 8.9+/-0.1) and 5-HT(7) receptors in guinea-pig cortex (pK(i) 8.3+/-0.2). 5-CT stimulated adenylyl cyclase activity in 5-HT(7(a))/HEK293 membranes (pEC(50) 7.5+/-0.1) and SB-269970-A (0.03 - 1 microM) inhibited the 5-CT concentration-response with no significant alteration in the maximal response. The pA(2) (8.5+/-0.2) for SB-269970-A agreed well with the pK(i) determined from [(3)H]-5-CT binding studies. 5-CT-stimulated adenylyl cyclase activity in guinea-pig hippocampal membranes (pEC(50) of 8.4+/-0.2) was inhibited by SB-269970-A (0.3 microM) with a pK(B) (8.3+/-0.1) in good agreement with its antagonist potency at the human cloned 5-HT(7(a)) receptor and its binding affinity at guinea-pig cortical membranes. 5-HT(7) receptor mRNA was highly expressed in human hypothalamus, amygdala, thalamus, hippocampus and testis. SB-269970-A was CNS penetrant (steady-state brain : blood ratio of ca. 0.83 : 1 in rats) but was rapidly cleared from the blood (CLb=ca. 140 ml min(-1) kg(-1)). [1]

---

Functional antagonist activity is assessed via inhibition of 5-CT-stimulated adenylyl cyclase in 5-HT7(a)/HEK293 membranes. Cells are incubated with SB-269970 (0.03–1 µM) and increasing concentrations of 5-CT. The pA2 value of 8.5 is calculated from the rightward shift of the 5-CT concentration-response curve without significant alteration of maximal response. In addition, the compound's effects on 5-HT efflux are evaluated by superfusing cells with 1 μM SB-269970 alone to confirm that it has no direct effect on serotonin release, distinguishing it from other serotonergic modulators.

Dissolved in saline; 10 mg/kg, 30 mg/kg; i.p.injection
C57BL6/J mice In this study, the effect of the 5-HT(7) receptor antagonist, SB-269970 ((R)-1-[3-hydroxy phenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl]pyrrolidine), was investigated on 5-HT release in the guinea-pig and rat cortex and the rat dorsal raphe nucleus (DRN), using the techniques of in vitro [(3)H]-5-HT release or fast cyclic voltammetry, respectively. 2. Cortical slices were loaded with [(3)H]-5-HT and release was evoked by electrical stimulation. 5-CT inhibited the evoked release of [(3)H]-5-HT in a concentration-dependent manner. SB-269970 had no significant effect on [(3)H]-5-HT release while the 5-HT(1B) receptor antagonist, SB-224289 significantly potentiated [(3)H]-5-HT release. In addition, SB-269970 was unable to attenuate the 5-CT-induced inhibition of release while SB-224289 produced a rightward shift of the 5-CT response, generating estimated pK(B) values of 7.8 and 7.6 at the guinea-pig and rat terminal 5-HT autoreceptors respectively. 3. Rat DRN slices were electrically stimulated and the evoked 5-HT efflux detected by voltammetric analysis. 8-OH-DPAT inhibited evoked 5-HT efflux and was fully reversed by WAY 100635. SB-269970 had no effect on either 5-HT efflux per se or 8-OH-DPAT-induced inhibition of 5-HT efflux. In addition, 5-CT inhibited 5-HT efflux in a concentration-dependent manner. SB-269970 was unable to attenuate the 5-CT-induced inhibition of 5-HT efflux. 4. In conclusion, we were unable to provide evidence to suggest a 5-HT autoreceptor role for 5-HT(7) receptors. However, investigations with more selective 5-HT(7) receptor agonists are needed to confirm the data reported here.[2]

---

---

In male C57BL/6 mice, SB-269970 is administered intraperitoneally at 3–30 mg/kg as a single dose to assess blockade of amphetamine- and ketamine-induced hyperactivity. In rat models, the compound is evaluated in conditioned avoidance response assays and prepulse inhibition paradigms to assess its antipsychotic-like effects. In guinea-pigs, 5-CT-induced hypothermia is used as a pharmacodynamic readout, with SB-269970 blocking this response with an ED50 of 2.96 mg/kg i.p. For pharmacokinetic studies, the compound is formulated in appropriate vehicles and administered via intraperitoneal or oral routes, with blood and brain tissue collected at various time points for analysis.

SB-269970 is CNS-penetrant with a steady-state brain-to-blood ratio of approximately 0.83:1 in rats. It is rapidly cleared from blood (CLb ≈ 140 mL/min/kg). Following a single 3 mg/kg dose, the compound is detectable in rat brain at 30 minutes (87 nM) and 60 minutes (58 nM). In guinea-pigs, brain levels average 31 nM and 51 nM at 30 and 60 minutes post-dose, respectively. The compound's brain penetration and favorable brain-to-blood ratio support its utility in studying central 5-HT7 receptor function. However, its rapid clearance from blood suggests that multiple dosing or continuous infusion may be required for sustained target engagement in longer-term studies.

Comprehensive toxicological data for SB-269970 are limited as the compound is primarily used for research purposes rather than therapeutic development. Safety data sheets indicate that toxicological effects have not been thoroughly studied, and the material should be considered hazardous until further information becomes available. Standard laboratory precautions should be observed during handling, including the use of appropriate personal protective equipment and working in a well-ventilated area. The compound has not been evaluated in formal toxicology studies for human use, and no data are available regarding genotoxicity, carcinogenicity, or reproductive toxicity.

[1]. Characterization of SB-269970-A, a selective 5-HT(7) receptor antagonist. Br J Pharmacol. 2000 Jun;130(3):539-48.

[2]. The effect of SB-269970, a 5-HT(7) receptor antagonist, on 5-HT release from serotonergic terminals and cell bodies. Br J Pharmacol. 2001 Apr;132(7):1574-80.

[3]. Effects of the selective 5-HT7 receptor antagonist SB-269970 and amisulpride on ketamine-induced schizophrenia-like deficits in rats. PLoS One. 2013 Jun 11;8(6):e66695.

[4]. The serotonin 5-HT7 receptor agonist LP-44 microinjected into the dorsal raphe nucleus suppresses REM sleep in the rat. Behav Brain Res. 2008 Aug 22;191(2):184-9.

3-[[(2R)-2-[2-(4-methyl-1-piperidinyl)ethyl]-1-pyrrolyl]sulfonyl]phenol is a sulfonamide compound. SB-269970 is an investigational drug developed by GlaxoSmithKline. Studies of this drug have shown that SB-269970 may act as a selective antagonist or inverse agonist of the 5-hydroxytryptamine receptor 7 (5-HT7).

---

SB-269970 has been extensively investigated in numerous preclinical studies for its antidepressant-like effects, showing rapid-onset antidepressant activity through modulation of dorsal raphe nucleus activity and subsequent cortical serotonin release. It has also been evaluated in models of psychosis and cognition, demonstrating efficacy in reversing amphetamine-induced disruptions. The compound has not progressed to clinical trials and remains a gold standard research tool for studying 5-HT7 receptor function in neurological and psychiatric disorders. A systematic review of 49 preclinical and 11 human studies has demonstrated antidepressant- or anxiolytic-related effects using compounds with at least moderate 5-HT7 receptor affinity, validating the receptor as a therapeutic target. SB-269970's role as the first selective 5-HT7 receptor antagonist has been instrumental in defining the receptor's biology and therapeutic potential.

C18H28N2O3S

352.49

352.18

C, 61.33; H, 8.01; N, 7.95; O, 13.62; S, 9.10

201038-74-6

SB-269970 hydrochloride; 261901-57-9

6604889

Solid powder

512.9ºC at 760 mmHg

264ºC

3.87E-11mmHg at 25°C

4.425

1

5

5

24

497

1

OC1=CC=CC(S(=O)(N2[C@@H](CCN3CCC(C)CC3)CCC2)=O)=C1

HWKROQUZSKPIKQ-MRXNPFEDSA-N

InChI=1S/C18H28N2O3S/c1-15-7-11-19(12-8-15)13-9-16-4-3-10-20(16)24(22,23)18-6-2-5-17(21)14-18/h2,5-6,14-16,21H,3-4,7-13H2,1H3/t16-/m1/s1

3-[(2R)-2-[2-(4-methylpiperidin-1-yl)ethyl]pyrrolidin-1-yl]sulfonylphenol

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

30%propylene glycol+ 5%Tween 80+ 65%D5W: 30.0mg/ml (77.13mM) (Please use freshly prepared in vivo formulations for optimal results.)