Design and optimization of selective azaindole amide M 1 positive allosteric modulators

Characterization of a Novel M1 Muscarinic Acetylcholine Receptor Positive Allosteric Modulator Radioligand, [3H]PT-1284

“…As shown in Fig. 10, for a cohort of 19 M 1 PAMs previously reported by our group (Davoren et al, 2016), a positive correlation (R 2 5 0.86) was found between the EC 50 values obtained using the M 1 mAChR FLIPR PAM assay and the binding pK i values determined with the [ 3 H]PT-1284 binding displacement assay. …”

Diverse Effects on M1 Signaling and Adverse Effect Liability within a Series of M1 Ago-PAMs

“…60 As shown in Table 4, the difluoro indoles 28a and 28c were potent M 1 PAMs on both human (EC 50 = 210 nM and EC 50 = 224 nM, respectively) and rat (EC 50 = 141 nM and EC 50 = 191 nM, respectively) receptors with comparable efficacies (86–92% ACh Max) and rat CNS penetration ( K p ’s = 0.11, K p,uu ’s = 0.02); however, they were both 5- to 14-fold less potent than 16 (hEC 50 = 31 nM, rEC 50 = 30 nM), 31 (hEC 50 = 59 nM, rEC 50 = 39 nM), 32 (hEC 50 = 48 nM, rEC 50 = 24 nM), and 33 (hEC 50 = 17 nM, rEC 50 = 18 nM) but with similar efficacies and K p ’s/ K p,uu ’s. Thus, absolute M 1 PAM potency was a differentiating point; however, 31 was similarly potent to the M 1 ago-PAMs ( 16 , 32 , and 33 ) that induced seizures.…”

It Is Important to Compute Intramolecular Hydrogen Bonding in Drug Design?

“…As an example, the bioactive conformation of a given ligand could be stabilized by IMHBs. This could reduce the conformational and translational entropy upon binding and result in stronger association [212,213,214,215]. Furthermore, the accessibility of polar atoms in a molecule could be decreased if IMHBs are established.…”