Design and Discovery of Functionally Selective Serotonin 2C (5-HT_2C) Receptor Agonists

On the basis of the structural similarity of our previous 5-HT_2C agonists with the melatonin receptor agonist tasimelteon and the putative biological cross-talk between serotonergic and melatonergic systems, a series of new (2,3-dihydro)­benzofuran-based compounds were designed and synthesized. The compounds were evaluated for their selectivity toward 5-HT_2A, 5-HT_2B, and 5-HT_2C receptors in the calcium flux assay with the ultimate goal to generate selective 5-HT_2C agonists. Selected compounds were studied for their functional selectivity by comparing their transduction efficiency at the G protein signaling pathway versus β-arrestin recruitment. The most functionally selective compound (+)-<b>7e</b> produced weak β-arrestin recruitment and also demonstrated less receptor desensitization compared to serotonin in both calcium flux and phosphoinositide (PI) hydrolysis assays. We report for the first time that selective 5-HT_2C agonists possessing weak β-arrestin recruitment can produce distinct receptor desensitization properties

Design and Synthesis of γ- and δ‑Lactam M₁ Positive Allosteric Modulators (PAMs): Convulsion and Cholinergic Toxicity of an M₁‑Selective PAM with Weak Agonist Activity

Recent data demonstrated that activation of the muscarinic M₁ 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 <b>1</b> (PF-06827443), is a potent, low-clearance, orally bioavailable, and CNS-penetrant M₁-selective PAM with minimal agonist activity. Compound <b>1</b> 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

Design and Synthesis of γ- and δ‑Lactam M₁ Positive Allosteric Modulators (PAMs): Convulsion and Cholinergic Toxicity of an M₁‑Selective PAM with Weak Agonist Activity

Recent data demonstrated that activation of the muscarinic M₁ 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 <b>1</b> (PF-06827443), is a potent, low-clearance, orally bioavailable, and CNS-penetrant M₁-selective PAM with minimal agonist activity. Compound <b>1</b> 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