Design, Synthesis, and Characterization of 4-Undecylpiperidine-2-carboxamides as Positive Allosteric Modulators of the Serotonin (5-HT) 5-HT_2C Receptor

Abstract

An impaired signaling capacity of the serotonin (5-HT) 5-HT receptor (5-HTR) has been implicated in the neurobehavioral processes that promote relapse vulnerability in cocaine use disorder (CUD). Restoration of the diminished 5-HTR signaling through positive allosteric modulation presents a novel therapeutic approach. Several new molecules with the 4-alkylpiperidine-2-carboxamide scaffold were designed, synthesized, and pharmacologically evaluated, leading to the discovery of selective 5-HTR positive allosteric modulators (PAMs). Compound 16 (CYD-1-79) potentiated 5-HT-evoked intracellular calcium release in cells stably expressing the human 5-HTR but not the 5-HTR cells. A topographically distinct allosteric site was identified based on the newly solved 5-HTR structure. Compound 16 modulated 5-HTR-mediated spontaneous ambulation, partially substituted for the training dose of the 5-HTR agonist WAY163909, synergized with a low dose of WAY163909 to substitute fully for the stimulus effects of WAY163909, and attenuated relapse vulnerability as assessed in a rodent self-administration model, indicating its therapeutic promise for CUD.

Allosteric Modulation of Class A GPCRs: Targets, Agents, and Emerging Concepts

“…Recently, our group reported CYD-1–79 ( 3 ), with a 4-alkylpiperidine-2-carboxamide scaffold, as a selective 5-HT 2C R PAM presenting a promising in vitro and in vivo profile for the treatment of cocaine use disorder (CUD). 51 Unlike 1 , 3 (Figure 3) functions as a pure PAM to potentiate 5-HT-evoked calcium mobilization in CHO cells expressing human 5-HT 2C R but exhibits no intrinsic activation of calcium mobilization. When investigated in preclinical pharmacokinetic (PK) and rodent efficacy studies, 3 displays measurable blood—brain barrier permeability and significantly suppresses motor impulsivity and cue reactivity assessed as lever presses for cocaine-associated cues in a rodent cocaine self-administration assay.…”

Positive-allosteric modulation of the 5-HT2C receptor: implications for neuropsychopharmacology and neurotherapeutics

“…A wide array of validated technologies can quantify motion. These range from active sensors that move along with the body (e.g., accelerometers, gyroscopes), passive "line of sight" technologies (e.g., cameras, thermal sensors, and lasers), passive technologies that can detect motion through walls (e.g., radio wave sensors) and positioning technologies (e.g., GPS, satellite imaging) [5]. It is now possible to track individual contractions of facial muscles (used in computer vision and analysis of micro emotions), complex motions such as smoking or drinking coffee [6] or even the movement of an individual across a global geographic field.…”

“…), it is possible to elicit gait speed, gait patterns and spatial location. Using clinical correlation, we have established that these data can serve as markers of apathy, pacing, and disrupted circadian rhythms in patients with dementia [5].…”

“…In 2003, chemical library screening resulted in the discovery of an analogue of the antibiotic lincomycin, PNU-69176E, as a selective 5-HT 2C R PAM [3]. In 2012, Zhou and colleagues optimized the synthetic route to generate PNU-69176E and its diastereomer [4], and we have recently designed, synthesized and characterized a series of new chemical entities as selective 5-HT 2C R PAMs [5]. Several molecules potentiated 5-HT 2C R-evoked signaling in vitro without displaying 5-HT 2C R efficacy or altering 5-HT 2A R signaling.…”

“…Serotonin binds to the orthosteric site to generate downstream signaling. The 5-HT 2C R PAM CYD-1-79 (cis-4-alkylpiperidine-2-carboxamide series) increases 5-HT efficacy through actions at the allosteric site[5] Published online: 10 September 2018…”