Synonym
PF-06767832; PF 06767832; PF06767832; PF-6767832; PF 6767832; PF6767832
IUPAC/Chemical Name
N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-5-methyl-4-(4-(thiazol-4-yl)benzyl)picolinamide
InChi Key
VVZZHFMLRHJXTO-RXVVDRJESA-N
InChi Code
InChI=1S/C22H23N3O3S/c1-14-10-23-19(22(27)25-18-6-7-28-11-21(18)26)9-17(14)8-15-2-4-16(5-3-15)20-12-29-13-24-20/h2-5,9-10,12-13,18,21,26H,6-8,11H2,1H3,(H,25,27)/t18-,21-/m0/s1
SMILES Code
O=C(C1=NC=C(C)C(CC2=CC=C(C3=CSC=N3)C=C2)=C1)N[C@@H]4[C@@H](O)COCC4
Purity
>98% (or refer to the Certificate of Analysis)
Shipping Condition
Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition
Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility
Soluble in DMSO, not in water
Shelf Life
>2 years if stored properly
Drug Formulation
This drug may be formulated in DMSO
Stock Solution Storage
0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code
2934.99.9001
More Info
It is hypothesized that selective muscarinic M1 subtype activation could be a strategy to provide cognitive benefits to schizophrenia and Alzheimer’s disease patients while minimizing the cholinergic side effects observed with nonselective muscarinic orthosteric agonists. Selective activation of M1 with a
positive allosteric modulator (PAM) has emerged as a new approach to achieve selective M1 activation.
Biological target:
Biological target:
PF-06767832 is a high quality M1 selective PAM (M1 PAM EC50 = 60 nM; M2-M5 PAM EC50 > 10 microM; CNS MPO = 4.9).
In vitro activity:
Compound 38 (PF-06767832) is a high quality M1 selective PAM that has well-aligned physicochemical properties, good brain penetration and pharmacokinetic properties. Extensive safety profiling suggested that despite being devoid of mAChR M2/M3 subtype activity, compound 38 still carries gastrointestinal and cardiovascular side effects. These data provide strong evidence that M1 activation contributes to the cholinergic liabilities that were previously attributed to activation of the M2 and M3 receptors.
Reference: J Med Chem. 2016 Jul 14;59(13):6313-28. https://pubmed.ncbi.nlm.nih.gov/27275946/
In vivo activity:
Systemic administration of PF-06767832 (1 mg/kg, i.p.) also reduced operant sucrose self-administration, suggesting the actions of the M1 receptor may be non-selective across drug and natural rewards. Finally, to understand whether this reduction extended to natural consummatory behaviors, this study assessed home cage standard chow and water consumption. M1 enhancement via systemic PF-06767832 administration reduced food and water consumption. Together these results suggest the M1 PAM-agonist, PF-06767832, non-specifically reduces consummatory behaviors that are not associated with motivational strength for the reward.
Reference: Pharmacol Res Perspect. 2022 Feb;10(1):e00907. https://pubmed.ncbi.nlm.nih.gov/34962108/
Preparing Stock Solutions
The following data is based on the
product
molecular weight
409.50
Batch specific molecular weights may vary
from batch to batch
due to the degree of hydration, which will
affect the solvent
volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass |
1 mg |
5 mg |
10 mg |
| 1 mM |
1.15 mL |
5.76 mL |
11.51 mL |
| 5 mM |
0.23 mL |
1.15 mL |
2.3 mL |
| 10 mM |
0.12 mL |
0.58 mL |
1.15 mL |
| 50 mM |
0.02 mL |
0.12 mL |
0.23 mL |
Formulation protocol:
1. Walker LC, Campbell EJ, Huckstep KL, Chen NA, Langmead CJ, Lawrence AJ. M1 muscarinic receptor activation decreases alcohol consumption via a reduction in consummatory behavior. Pharmacol Res Perspect. 2022 Feb;10(1):e00907. doi: 10.1002/prp2.907. PMID: 34962108; PMCID: PMC8929368.
2. Davoren JE, Lee CW, Garnsey M, Brodney MA, Cordes J, Dlugolenski K, Edgerton JR, Harris AR, Helal CJ, Jenkinson S, Kauffman GW, Kenakin TP, Lazzaro JT, Lotarski SM, Mao Y, Nason DM, Northcott C, Nottebaum L, O'Neil SV, Pettersen B, Popiolek M, Reinhart V, Salomon-Ferrer R, Steyn SJ, Webb D, Zhang L, Grimwood S. Discovery of the Potent and Selective M1 PAM-Agonist N-[(3R,4S)-3-Hydroxytetrahydro-2H-pyran-4-yl]-5-methyl-4-[4-(1,3-thiazol-4-yl)benzyl]pyridine-2-carboxamide (PF-06767832): Evaluation of Efficacy and Cholinergic Side Effects. J Med Chem. 2016 Jul 14;59(13):6313-28. doi: 10.1021/acs.jmedchem.6b00544. Epub 2016 Jul 1. PMID: 27275946.
In vitro protocol:
1. Davoren JE, Lee CW, Garnsey M, Brodney MA, Cordes J, Dlugolenski K, Edgerton JR, Harris AR, Helal CJ, Jenkinson S, Kauffman GW, Kenakin TP, Lazzaro JT, Lotarski SM, Mao Y, Nason DM, Northcott C, Nottebaum L, O'Neil SV, Pettersen B, Popiolek M, Reinhart V, Salomon-Ferrer R, Steyn SJ, Webb D, Zhang L, Grimwood S. Discovery of the Potent and Selective M1 PAM-Agonist N-[(3R,4S)-3-Hydroxytetrahydro-2H-pyran-4-yl]-5-methyl-4-[4-(1,3-thiazol-4-yl)benzyl]pyridine-2-carboxamide (PF-06767832): Evaluation of Efficacy and Cholinergic Side Effects. J Med Chem. 2016 Jul 14;59(13):6313-28. doi: 10.1021/acs.jmedchem.6b00544. Epub 2016 Jul 1. PMID: 27275946.
In vivo protocol:
1. Walker LC, Campbell EJ, Huckstep KL, Chen NA, Langmead CJ, Lawrence AJ. M1 muscarinic receptor activation decreases alcohol consumption via a reduction in consummatory behavior. Pharmacol Res Perspect. 2022 Feb;10(1):e00907. doi: 10.1002/prp2.907. PMID: 34962108; PMCID: PMC8929368.
2. Davoren JE, Lee CW, Garnsey M, Brodney MA, Cordes J, Dlugolenski K, Edgerton JR, Harris AR, Helal CJ, Jenkinson S, Kauffman GW, Kenakin TP, Lazzaro JT, Lotarski SM, Mao Y, Nason DM, Northcott C, Nottebaum L, O'Neil SV, Pettersen B, Popiolek M, Reinhart V, Salomon-Ferrer R, Steyn SJ, Webb D, Zhang L, Grimwood S. Discovery of the Potent and Selective M1 PAM-Agonist N-[(3R,4S)-3-Hydroxytetrahydro-2H-pyran-4-yl]-5-methyl-4-[4-(1,3-thiazol-4-yl)benzyl]pyridine-2-carboxamide (PF-06767832): Evaluation of Efficacy and Cholinergic Side Effects. J Med Chem. 2016 Jul 14;59(13):6313-28. doi: 10.1021/acs.jmedchem.6b00544. Epub 2016 Jul 1. PMID: 27275946.
1: Davoren JE, Lee CW, Garnsey M, Brodney MA, Cordes J, Dlugolenski K, Edgerton JR, Harris AR, Helal CJ, Jenkinson S, Kauffman GW, Kenakin TP, Lazzaro JT, Lotarski SM, Mao Y, Nason DM, Northcott C, Nottebaum L, O'Neil SV, Pettersen B, Popiolek M, Reinhart V, Salomon-Ferrer R, Steyn SJ, Webb D, Zhang L, Grimwood S. Discovery of the Potent and Selective M1 PAM-Agonist N-[(3R,4S)-3-Hydroxytetrahydro-2H-pyran-4-yl]-5-methyl-4-[4-(1,3-thiazol-4-yl)ben zyl]pyridine-2-carboxamide (PF-06767832): Evaluation of Efficacy and Cholinergic Side Effects. J Med Chem. 2016 Jul 1. [Epub ahead of print] PubMed PMID: 27275946.
