Receptor target profile

“LB-102, a novel, once-daily, oral investigational small molecule, is a selective antagonist of D2, D3, and 5HT-7 receptors that is being advanced as a potential first benzamide in the U.S. for the treatment of neuropsychiatric disorders.” (opens the source at this quote in a new tab)

“LB-102 (Fig. 1) is a N methylated version of amisulpride, a dopamine inhibitor developed in the 1980s and approved in more than 50 countries outside the United States for the treatment of schizophrenia.” (opens the source at this quote in a new tab)

Receptor binding affinities of LB-102, amisulpride, and their enantiomers

Antagonist	D2 KI (nM)	5-HT7 KI (nM)
Amisulpride, S enantiomer	“n.d.”	“900 ± 1300”
Amisulpride, racemate	“1.1 ± 0.12”	“44 ± 3”
Amisulpride, R enantiomer	“n.d.”	“22 ± 1.5”
LB-102 (racemate)	“0.82 ± 0.02”	“31 ± 1”
LB-103 (S enantiomer of LB-102)	“0.4 ± 0.04”	“>1000”
LB-104 (R enantiomer of LB-102)	“14.4 ± 2.2”	“15.6 ± 0.9”

“As well, within experimental uncertainty, LB-102 and amisulpride bind to the D2 receptor with a Kd of 1 nM.” (opens the source at this quote in a new tab)
“The racemic benzamide affinity for the 5-HT7 receptor is approximately 30-fold weaker than its D2 receptor affinity though potentially still pharmacologically relevant.” (opens the source at this quote in a new tab)

Enantiomer pharmacology: S enantiomer at D2 and D3, R enantiomer at 5-HT7

“Curiously, the studies herein reveal that racemic dosing is required to engage both targets since the D2 receptor has an almost 40-fold selectivity for the S enantiomer, while the 5-HT7 receptor has greater than 50-fold preference for the R enantiomer.” (opens the source at this quote in a new tab)
“The benzamides display polypharmacy if dosed as a racemate: antipsychotic activity is provided by targeting D2/3 receptors with the S enantiomer, while antidepressant effects are provided by targeting the 5-HT7 receptor with the R enantiomer.” (opens the source at this quote in a new tab)
“Based on the findings in this report, racemic LB-102 will be advanced to the clinic rather than the enantiomerically pure S LB-103.” (opens the source at this quote in a new tab)

Limits of the in vitro 5-HT7 data

“The absence of in vivo 5-HT7 receptor occupancy studies in animals or humans limits our ability to reliably model 5-HT7 in vivo occupancy since in vitro binding affinities rarely translate well to in vivo occupancies.” (opens the source at this quote in a new tab)
“Reliably modeling 5-HT7 occupancy in humans will require a competing PET ligand study, as has been done with the D2/3 receptors.” (opens the source at this quote in a new tab)

D3 receptor affinity and comparison with amisulpride

“Binding to D2 and D3 receptors was similar to amisulpride (Ki of 2.8 nM against D2 and 3.2 nM against D3).” (opens the source at this quote in a new tab)

“LB-102 bound similarly to the dopamine D2 and D3 receptors, with a Ki (inhibition constant) of 0.82 nM compared to amisulpride’s reported Ki of 1.1 nM, and had a similar affinity for the 5-HT7 receptor with a Ki of 31 nM compared to amisulpride’s reported Ki of 44 nM.” (opens the source at this quote in a new tab)

“LB-102 was specifically engineered to address the blood-brain barrier issues observed with amisulpride: LB-102 retains high-affinity antagonism at D2/D3 (Ki = 0.8nM) and serotonin (5-HT7; Kᵢ = 31nM) receptors with greater passive membrane diffusion into the brain.” (opens the source at this quote in a new tab)

Off-target receptor binding

“Compared to other commonly prescribed antipsychotic drugs, both LB-102 and amisulpride have weaker binding to other off-target CNS receptors that are commonly associated with adverse side effects such as anxiety, weight gain, or metabolic syndrome such as 5HT2C.” (opens the source at this quote in a new tab)

Rationale for N-methylation of amisulpride

“Selective N-methylation of amisulpride produces LB-102/LB-103, designed to decrease hydrophilicity to improve BBB permeability, increase brain and lower plasma exposure.” (opens the source at this quote in a new tab)

“The methylation we incorporated into LB-102 was designed to improve the tolerability and efficacy profile of amisulpride by addressing its shortcomings, such as limited blood-brain barrier, or BBB, permeability and dosing frequency.” (opens the source at this quote in a new tab)
“Enhanced BBB permeability was expected to improve the potency of the molecule with respect to dopamine receptor binding and enable the use of lower doses compared with amisulpride.” (opens the source at this quote in a new tab)
“The use of lower doses was hypothesized to improve the tolerability profile.” (opens the source at this quote in a new tab)

“Because of amisulpride’s poor membrane permeability, high doses are required to achieve plasma concentrations associated with dopamine RO > 60%.” (opens the source at this quote in a new tab)

Lipophilicity of LB-102 and amisulpride

“the measured Log P for amisulpride was 1.52 while that for LB-102 was 1.72; the measured pKas for amisulpride and LB-102 were 9.32 and 9.36, respectively” (opens the source at this quote in a new tab)
“The role of the methyl group in this equilibrium is unclear and was beyond the scope of the current work.” (opens the source at this quote in a new tab)

Characterization in an independent narrative review

“LB-102, a newly identified N-methylated analog of amisulpride, exhibits enhanced lipophilicity at lower doses, as demonstrated in a phase 1 study, indicating significant promise for therapeutic applications.” (opens the source at this quote in a new tab)

Dose-dependent presynaptic and postsynaptic dopamine receptor effects

“Moreover, at low doses, LB-102 and amisulpride have selectivity for pre-synaptic autoreceptors that serves to increase dopamine signaling which is underactive in depression.” (opens the source at this quote in a new tab)

“At high doses, postsynaptic D2/D3 receptor blockade suppresses dopamine signaling, which is overactive in psychosis” (opens the source at this quote in a new tab)

Class context: limbic selectivity of amisulpride

“In vitro, amisulpride has high affinity and selectivity for the human dopamine D2 (Ki = 2.8 nM) and D3 (Ki = 3.2 nM) receptors.” (opens the source at this quote in a new tab)
“In vivo, it displays a degree of limbic selectivity and a preferential effect, at low doses, on dopamine D2/D3 autoreceptors.” (opens the source at this quote in a new tab)

“In animals, at high doses it blocks post-synaptic D2 receptors located in the limbic structures in preference to those in the striatum.” (opens the source at this quote in a new tab)
“In addition, the reduced tendency of amisulpride to produce extrapyramidal side effects may be related to its preferential limbic activity.” (opens the source at this quote in a new tab)

Class context: 5-HT7 antagonism and the antidepressant activity of amisulpride

“The work of Abbas et al., consisting of rodent in vivo studies, as well as the examination of a panel of off-target receptors, identified the serotonin 5-HT7 receptor as the likely mediator of amisulpride’s antidepressant activity.” (opens the source at this quote in a new tab)

“These results indicate that 5-HT7a receptor antagonism, and not D2/D3 receptor antagonism, likely underlies the antidepressant actions of amisulpride.” (opens the source at this quote in a new tab)

Limbic versus striatal selectivity measured for LB-102

No evidence found.

In vivo 5-HT7 receptor occupancy of LB-102

No evidence found.