Mu-opioid receptor (MOR) – binds to an allosteric site distinct from the orthosteric site. In β-arrestin recruitment assay, BMS-986122 had Kb = 5 μM and cooperativity factor α = 7 (with endomorphin-I). In [³⁵S]GTPγS binding in C6μ membranes, it enhanced DAMGO potency (EC50 shift) with similar parameters. No binding to delta-opioid receptor detected. [1]

BMS-986122 promotes the recruitment of β-arrestin in U2OS-OPRM1 human osteosarcoma cells that express u-opioid receptors in response to endorphin 1 (EC50=3 μM). BMS-986122 upregulates the suppression of forskolin-stimulated adenylyl cyclase activity in CHO cells that express human recombinant u-opioid linkers, which is activated by endorphin 1 (EC50=8.9 μM). In mouse meninges, BMS-986122 increases DAMGO-mediated binding of [35S]GTPγS and, to some extent, seems to be a positive affinity modulator of DAMGO binding via u-opioid uptake [1]. In CHO cells expressing human u-opioid receptors, BMS-986122 enhances the ability of the endogenous opioid methionine-enkephalin (Met-Enk) to stimulate G protein activity, while it is inactive on its own and less effective than β-arrestin Enhanced G-protein activation recruitment. BMS-986122 amplifies Met-Enk's ability to suppress GABA release in the periaqueductal gray matter, a critical area for anti-injury effects [2]. BMS-986122 possesses the similarly related δ-OR and is selective for μ-OR. A quiet allosteric modulator of δ-OR and κ-OR is BMS-986122 [3].

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BMS-986122 (0.39–100 μM) produced concentration-dependent leftward shifts in endomorphin-I-stimulated β-arrestin recruitment in U2OS-OPRM1 cells, with EC50 = 3.0 μM (95% CI: 1.9–3.9 μM) in PAM mode and no agonist activity alone. [1]
BMS-986122 (1–100 μM) potentiated inhibition of forskolin-stimulated cAMP accumulation by endomorphin-I (30 pM) in CHO-μ cells, with EC50 = 8.9 μM (6.1–13.1 μM); it also showed weak agonist activity (EC50 = 41 μM, Emax = 60%) at high concentrations. [1]
BMS-986122 (10 μM) enhanced DAMGO-stimulated [³⁵S]GTPγS binding in C6μ membranes, shifting DAMGO EC50 from 222 nM to 32 nM (7-fold leftward) with no change in maximal stimulation. It also shifted morphine potency 3-fold (EC50 from 110 nM to 38 nM) and increased morphine Emax from 42% to 74% of DAMGO response. [1]
BMS-986122 (10 μM) increased DAMGO binding affinity (Ki) in competition with [³H]diprenorphine in C6μ membranes: DAMGO Ki shifted from 340 nM to 56 nM (6-fold) in low-affinity buffer (with Na⁺/GTPγS), and from 2.21 nM to 0.51 nM (4-fold) in high-affinity buffer. It did not affect [³H]diprenorphine Kd. [1]
BMS-986122 (10 μM) enhanced Met-Enk-stimulated [³⁵S]GTPγS binding in mouse brain homogenates: Met-Enk EC50 shifted from 148 nM to 14.5 nM (10-fold) in PAG homogenates; in whole brain, it enhanced DAMGO potency 6.6-fold (EC50 from 484 nM to 73.1 nM), morphine 4.8-fold (from 2592 nM to 543 nM), and methadone 8-fold (from 447 nM to 55 nM). No agonist activity alone. [2]
In CHO cells expressing hMOR, BMS-986122 (10 μM) enhanced Met-Enk-stimulated [³⁵S]GTPγS binding by 7.8-fold (EC50 from 18.2 nM to 2.3 nM) and β-arrestin recruitment by only 1.8-fold (EC50 from 11.4 nM to 6.2 nM), indicating a modest bias toward G protein (bias factor 4.3 vs Met-Enk alone). [2]
BMS-986122 (1–100 μM) potentiated Met-Enk inhibition of GABA release in rat PAG slices, shifting Met-Enk potency from 612 nM to 97.7 nM (6.3-fold) with no effect alone on mIPSC frequency. [2]

BMS-986122 (i.c.v. 0.05–1.5 nmol) alone produced dose- and time-dependent antinociception in the hot-plate test in C57BL/6 mice, lasting <15 min, which was blocked by the irreversible MOR antagonist β-FNA (5 mg/kg i.p., 24 h pretreatment). [2]
BMS-986122 (0.05–0.15 nmol i.c.v.) enhanced the antinociceptive effect of a subeffective dose of methadone (3 μg i.c.v.) or systemic methadone (5.6 mg/kg i.p.) and morphine (32 mg/kg i.p.) in the hot-plate test, producing robust and prolonged effects (up to 60 min). [2]
BMS-986122 (0.15 nmol i.c.v.) potentiated the antinociceptive effect of the enkephalinase inhibitor RB-101 (50 μg i.c.v.) in the hot-plate test, and also enhanced swim stress-induced antinociception (15 min swim) in a naloxone-reversible manner. [2]
In 129S1/SvlmJ mice, systemic BMS-986122 (3.2–10 mg/kg i.p.) produced antinociception in the warm water tail-withdrawal test (55°C) with maximal effect at 10 mg/kg lasting 60 min, blocked by naloxone (10 mg/kg i.p.). The effect was lost after repeated handling/injections, suggesting habituation and reduced endogenous opioid release. [2]
BMS-986122 (10 mg/kg i.p.) reversed mechanical allodynia in carrageenan-induced inflammatory pain (bilateral and unilateral) and in CFA-induced persistent inflammation (over 3 days) in 129S1/Svlmj mice, as measured by von Frey thresholds; effects were naloxone-reversible. [2]
BMS-986122 (10 mg/kg i.p.) restored acetic acid-induced depression of nesting behavior in mice, whereas morphine (10 mg/kg) did not. [2]

[³⁵S]GTPγS binding assays: Membranes (from mouse brain, PAG, or CHO-hMOR cells) were incubated with GDP (10–30 μM), [³⁵S]GTPγS (0.1–0.5 nM), and varying concentrations of agonist with or without 10 μM BMS-986122 for 5–15 min at 25–30°C. Bound radioactivity was collected by filtration and counted. Data were fit to logistic equation to obtain EC50 and Emax. [1][2]
Receptor binding assays: [³H]diprenorphine saturation and competition binding were performed using C6μ membranes (5–10 μg protein) incubated with 0–4 nM [³H]diprenorphine or 0.2–0.3 nM [³H]diprenorphine plus increasing DAMGO, with or without 10 μM BMS-986122, in buffer containing 100 mM NaCl, 10 μM GTPγS, 5 mM MgCl₂, and 50 mM Tris-HCl (pH 7.4) at room temperature for 60–80 min. Nonspecific binding defined by 10 μM naloxone. Filters were counted. Kd and Ki calculated by nonlinear regression. [1]

β-arrestin recruitment assay (PathHunter): U2OS cells expressing PK-tagged OPRM1 and β-arrestin 2 fusion were incubated with compounds and detection reagents; luminescence was measured. BMS-986122 was tested in agonist mode (alone) and PAM mode (with low EC10 endomorphin-I or Met-Enk). EC50 values were derived from concentration-response curves. [1][2]
cAMP accumulation assay (HTRF): CHO-μ cells were incubated with forskolin (1 μM) and test compounds; cAMP levels were measured by homogenous time-resolved fluorescence. BMS-986122 was tested for potentiation of low-dose endomorphin-I (30 pM) and for agonist activity alone. [1]

For i.c.v. injections in C57BL/6 mice: BMS-986122 was dissolved in 1% DMSO, 1% alkamuls, and 98% sterile water; administered at 0.05–1.5 nmol (23–670 ng) in 5 μL via intracerebroventricular route (i.c.v.). Methadone (i.c.v.) was dissolved similarly. RB-101 (i.c.v.) was dissolved in 20% (2-hydroxypropyl)-β-cyclodextrin. For systemic (i.p.) injections in 129S1/SvlmJ mice: BMS-986122 was dissolved in 60% sterile water, 20% ethanol, and 20% ethoxylated castor oil; administered at 3.2–10 mg/kg (maximum solubility) in a volume of 10 mL/kg. Morphine, methadone, naloxone, and β-FNA were dissolved in saline or water and given i.p. or s.c. as indicated. Behavioral tests (hot-plate at 52°C, tail-withdrawal at 55°C, von Frey, nesting, CPP, fecal boli count, respiration monitoring) were performed at various time points post-injection, with cutoff times to prevent tissue damage. All procedures followed IACUC guidelines. [2]

Plasma and brain concentrations after i.p. administration of 10 mg/kg BMS-986122 in 129S1/SvlmJ mice: at 1 h post-injection, mean plasma concentration was 397 ± 100 ng/g (n=9), and mean brain concentration was 127 ± 16 ng/mL (n=15), corresponding to ~900 nM and ~280 nM, respectively, with a plasma:brain ratio of 3:1. [2]
At 300 nM (brain relevant concentration), BMS-986122 produced a 3.9-fold shift in Met-Enk potency in [³⁵S]GTPγS binding in hMOR-CHO membranes (EC50 from 10.2 nM to 2.6 nM). [2]

BMS-986122 (10 mg/kg i.p.) did not produce constipation (fecal boli count similar to vehicle) in 129S1/SvlmJ mice, whereas morphine (10 mg/kg) significantly reduced fecal output. [2]
BMS-986122 (10 mg/kg i.p.) did not produce conditioned place preference (CPP) in 129S1/SvlmJ mice over 5-day conditioning, whereas morphine (10 mg/kg) showed significant preference. [2]
BMS-986122 (10 mg/kg i.p.) produced a small but significant respiratory depression (measured by breathing rate) that was reversed by naloxone, but the depression was significantly less than that caused by morphine (10 mg/kg). A lower dose of 3.2 mg/kg had no effect. [2]

[1]. Discovery of positive allosteric modulators and silent allosteric modulators of the μ-opioid receptor. Proc Natl Acad Sci U S A. 2013;110(26):10830-10835.

[2]. Positive allosteric modulation of the mu-opioid receptor produces analgesia with reduced side effects. Proc Natl Acad Sci U S A. 2021;118(16):e2000017118.

[3]. Livingston KE, Alt A, Canals M, Traynor JR. Pharmacologic Evidence for a Putative Conserved Allosteric Site on Opioid Receptors. Mol Pharmacol. 2018;93(2):157-167.

BMS-986122 is a positive allosteric modulator of the mu-opioid receptor, discovered via high-throughput screening using a β-arrestin recruitment assay. It is selective for MOR over delta-opioid receptor. It does not compete with orthosteric ligands (no binding to orthosteric site). It enhances both affinity and efficacy of orthosteric agonists, including endogenous peptides (Met-Enk, endomorphin-1) and exogenous opioids (DAMGO, morphine, methadone). It shows probe dependence, with varying degrees of potentiation for different agonists. In vivo, it produces analgesia by potentiating endogenous opioid peptide release during pain/stress, and exhibits reduced typical opioid side effects. Silent allosteric modulators (SAMs) BMS-986123 and BMS-986124 can block its PAM activity, confirming allosteric site specificity. The compound has been studied in mouse models of acute and inflammatory pain and shows potential as a safer analgesic. [1][2]

C16H15BRCLNO3S2

448.782200098038

446.936

313669-88-4

4644453

White to off-white solid powder

1.6±0.1 g/cm3

567.2±60.0 °C at 760 mmHg

296.8±32.9 °C

0.0±1.6 mmHg at 25°C

1.648

5.14

0

5

4

24

522

0

S1CCN(S(C2=CC=C(Cl)C=C2)(=O)=O)C1C1=CC=C(OC)C(Br)=C1

PNGJPVDGZNPZHY-UHFFFAOYSA-N

InChI=1S/C16H15BrClNO3S2/c1-22-15-7-2-11(10-14(15)17)16-19(8-9-23-16)24(20,21)13-5-3-12(18)4-6-13/h2-7,10,16H,8-9H2,1H3

2-(3-bromo-4-methoxyphenyl)-3-(4-chlorophenyl)sulfonyl-1,3-thiazolidine

BMS-986122 BMS 986122 BMS986122.

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)

DMSO : ~100 mg/mL (~222.83 mM)

Solubility in Formulation 1: 2.5 mg/mL (5.57 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (5.57 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)