101. Design and Synthesis of γ- and δ-Lactam M 1 Positive Allosteric Modulators (PAMs): Convulsion and Cholinergic Toxicity of an M 1 -Selective PAM with Weak Agonist Activity.
- Author
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Davoren JE, Garnsey M, Pettersen B, Brodney MA, Edgerton JR, Fortin JP, Grimwood S, Harris AR, Jenkinson S, Kenakin T, Lazzaro JT, Lee CW, Lotarski SM, Nottebaum L, O'Neil SV, Popiolek M, Ramsey S, Steyn SJ, Thorn CA, Zhang L, and Webb D
- Subjects
- Allosteric Regulation, Amphetamine pharmacology, Animals, Ataxia chemically induced, Diarrhea chemically induced, Dogs, Donepezil, Drug Design, Female, Humans, Indans pharmacology, Isoindoles administration & dosage, Isoindoles chemical synthesis, Isoindoles toxicity, Lactams administration & dosage, Lactams chemical synthesis, Lactams toxicity, Male, Mice, Inbred C57BL, Microsomes, Liver metabolism, Oxazoles administration & dosage, Oxazoles chemical synthesis, Oxazoles toxicity, Piperidines pharmacology, Rats, Wistar, Receptor, Muscarinic M1 antagonists & inhibitors, Scopolamine pharmacology, Structure-Activity Relationship, Sulfonamides pharmacology, Thiadiazoles pharmacology, Vomiting chemically induced, Isoindoles pharmacology, Lactams pharmacology, Oxazoles pharmacology, Receptor, Muscarinic M1 agonists, Seizures chemically induced
- Abstract
Recent data demonstrated that activation of the muscarinic M
1 receptor by a subtype-selective positive allosteric modulator (PAM) contributes to the gastrointestinal (GI) and cardiovascular (CV) cholinergic adverse events (AEs) previously attributed to M2 and M3 activation. These studies were conducted using PAMs that also exhibited allosteric agonist activity, leaving open the possibility that direct activation by allosteric agonism, rather than allosteric modulation, could be responsible for the adverse effects. This article describes the design and synthesis of lactam-derived M1 PAMs that address this hypothesis. The lead molecule from this series, compound 1 (PF-06827443), is a potent, low-clearance, orally bioavailable, and CNS-penetrant M1 -selective PAM with minimal agonist activity. Compound 1 was tested in dose escalation studies in rats and dogs and was found to induce cholinergic AEs and convulsion at therapeutic indices similar to previous compounds with more agonist activity. These findings provide preliminary evidence that positive allosteric modulation of M1 is sufficient to elicit cholinergic AEs.- Published
- 2017
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