TABLE 1.
Summary of muscarinic acetylcholine receptor (mAChR) ligands reported to be selective for M1
| Name | Institution year |
M1 | M2–M5 | Ancillary | DMPK | In vitro | In vivo |
|---|---|---|---|---|---|---|---|
| AC-42 (21)a | Acadia, 2002 | 320 nm | M5 EC50 = 6.93 µm | hD2Ki = 20 nm, 5HT2BKi = 450 nm |
Data not available | No effects in native tissue |
Data not available |
| AC-260584 (22)a | Acadia, 2008 | 41 nm | M2 IC50 >10 µm, M3 EC50 = 5.9 µm, M4 IC50 >10 µm, M5 EC50 = 1.0 µm |
hD2Ki = 50 nm, 5HT2BKi = 1.59 µm |
High clearance, 26% oral bioavailability |
Promotes Gαq-mediated signaling, reduced activation of arrestin signaling |
Increases ERK1/2 phosphorylation in mouse hippocampus; improvement in NOR mouse model |
| 77-LH-28-1 (23)a | GSK, 2008 | 8nM | M2 EC50 >765 nm, M3 EC50 = 159 nm, M4 EC50 >10 µm, M5 EC50 = 206 nm |
hD2Ki = 60 nm, 5HT2BKi = 950 nm |
B:P = 4, rapidly cleared, subcutaneous admin. optimal |
Stimulate CA1 cell firing and gamma frequency oscillations in rat hippocampus |
Enhances NMDA-mediated neuronal excitation in hippocampus |
| TBPB (24) | Merck, Vanderbilt, 2006 |
289 nm | M2 IC50 = 1.1 µm, M3 IC50 = 3.0 µm, M4 IC50 = 415 nm, M5 IC50 = 10 µm |
hD2 IC50 = 2.6 µm | Data not available | Promotes Gαq-mediated signaling, reduced activation of arrestin signaling, enhances sAPPα, potentiates NMDA receptor currents |
Reverses amphetamine hyperlocomotion in rat model |
| VU0357017 (34) | Vanderbilt, 2008 |
198 nm (16 µm)b |
M2–M5 >30 µm | <50% 68 GPCRs, functional D2 antagonist |
Low-moderate clearance, CNS penetrant, dosable in saline |
Stimulates Gαq-signaling, little effect on arrestin signaling; efficacious in hippocampus, little effect in other brain regions |
Effective in contextual fear conditioning model; inactive in spatial memory and AHL reversal |
| VU0364572 (35) | Vanderbilt, 2011 |
110 nm
(2.3 µm)b |
M2–M5 >30 µm | <30% 68 GPCRs, no D2 antagonism |
Low-moderate clearance, CNS penetrant, oral bioavailable |
Stimulates Gαq-signaling, littleeffect on arrestin signaling;efficacious in hippocampus, little effect in other brain regions |
Effective in contextual fear conditioning and spatial memory; inactive in AHL reversal |
| VU0409066 (36) | Vanderbilt, 2012 |
59 nm | M2 EC50 = 1.8 µm, M3 EC50 >10 µm, M4 EC50 >10 µm, M5 EC50 = 3.7 µm |
Data not available | High clearance, t1/2 = 46 min, orally bioavailable |
Enhance sAPPα | Data not available |
| VU0415371 (37) | Vanderbilt, 2012 |
110 nm | M2 IC50 >10 µm, M3 IC50 >10 µm, M4 IC50 = 3.1 µm, M5 IC50 = 4.9 µm |
Data not available | Data not available | Enhance sAPPα | Data not available |
| VU0413144 (38) | Vanderbilt, 2012 |
970 nm | M2–M5 >30 µm | Data not available | Data not available | Enhance sAPPα | Data not available |
| VU0420385 (39) | Vanderbilt, 2012 |
92 nm | M3 IC50 >10 µm, M4 IC50 >10 µm, M5 EC50 = 2.8 µm |
Data not available | Data not available | Enhance sAPPα | Data not available |
| VU0447360 (40) | Vanderbilt, 2012 |
47 nm | M4 IC50 >10 µm, M5 EC50 = 4.2 µm |
Data not available | Data not available | Enhance sAPPα | Data not available |
| NDMC (16)a | 115 nm | M2 EC50 = 295 nm, M3 EC50 = 31 nm, M4 EC50 = 1.23 µm, M5 EC50 = 50 nm |
hD2Ki = 180 nm, 5HT2CKi = 5 nm, 5HT2BKi = 4 nm |
Data not available | Data not available | Data not available | |
| Lu AE51090 (25) | Lundbeck, 2010 | 61 nm | M2Ki = 2.2 µm, M3Ki = 7.0 µm, M4Ki = 6.9 µm, M5Ki = 8.9 µm |
hα1AKi = 260 nm, hα1BKi = 910 nm, hH1Ki = 780 nm |
High clearance, low oral bioavailability, moderate B:P |
Data not available | Observable dose-dependent improvement in learning and memory in mouse Y-maze task |
| 26 | GSK, 2010 | 0.8 nm | M2 IC50 = 200 nm, M3 IC50 = 40 nm, M4 IC50 = 158 nm, M5 IC50 = 500 nm |
No inhibition in CEREP panel |
Good brain exposure (AUC = 1655 ng h/g), t1/2 = 2.3 hours, B:P = 0.9 |
Data not available | Data not available |
| 27 | GSK, 2010 | 10 nm | M2 IC50 = 2.5 µm, M3 IC50 = 5.0 µm, M4 IC50 = 3.2 µm, M5 IC50 = 6.3 µm |
Not determined | Oral bioavailability (F = 57%), brain exposure (AUC = 2221 ng h/g), t1/2 = 3.0 hours, Cl = 35 mL/min/kg |
Data not available | Data not available |
| 28 | GSK, 2010 | 8nM | M2 EC50 = 630 nm, M3 EC50 = 2.5 nm, M4 EC50 = 500 nm, M5 EC50 = 790 nm |
hERG IC50 = 12 µm, κ-OR 53% inhibition at 1µm, hD2Ki = 264 nm, 5HT2CKi = 52 nm, 5HT2BKi = 12 nm |
Cli <0.7 ml/min/kg, oral bioavailability (F = 49%), B:P = 0.6 |
Data not available | Increases cell firing of hippocampal CA1 cells; dose-dependent reversal of scopolamine model |
| 30 | GSK, 2010 | 10 nm | M2 EC50 = 2.5 µm, M3 EC50 = 4.0 µm, M4 EC50 = 790 nm, M5 EC50 = 1.0 µm |
CEREP panel sigma-receptor (75% inhibition at 10 µm) |
Cl = 23 mL/min/kg, free concentration brain = 261 nm, free concentration blood = 265 nm |
Data not available | Dose-dependent improvement of novel object recognition of temporal induced memory deficit in rat |
| Xanomelinea (17) | Eli Lilly, 1994 | 0.3 nm | M2 EC50 = 93 nm, M3 EC50 = 5 nm, M4 EC50 = 52 nm, M5 EC50 = 42 nm |
hD2Ki = 264 nm, 5HT2CKi = 52 nm, 5HT2BKi = 12 nm |
3–7% oral bioavailabilty, t1/2 = 32 min (rat) |
Enhance sAPPα | Reverses amphetamine hyperlocomotion in rat model; reverses apomorphine-induced deficit in PPI in rat model; effective in conditioned emotional response in rat model (anxiety); did not induce catalepsy in rats; advanced to Phase II and Phase III clinical trials |
Abbreviations: AHL, amphetamine-induced hyperlocomotion; CNS, central nervous system; DMPK, drug metabolism and pharmacokinetics; GPCR, G-protein-coupled receptor; NMDA, N-methyl-d-aspartate; NOR, novel object recognition; sAPPα, soluble amyloid precursor protein alpha.
a
Ancillary data taken from Ref. [49]; values differ somewhat from original report.
b
EC50 values reported are from TREx293 hM1 cell line with low receptor reserve. These data were taken from Ref. [67].