A Phase 2, Proof-of-concept, Multi-center, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of AT-5214 in Subjects with Moderate to Severe Facial Acne Vulgaris

Start Date01 Aug 2024

Sponsor / Collaborator-

NCT03084952 / Not yet recruitingPhase 2

A Phase 2, Randomized, Unicentric Clinical Trial With Dose Scaling for Safety, Tolerability and Efficacy Assessment of 18-Methoxycoronaridine Administered to Cutaneous Leishmaniasis Patients

It is a randomized phase II clinical study, unicentre aimed to evaluate the tolerability, safety and efficacy of 18-Methoxyoronaridine as a candidate of tegumentary leishmaniasis treatment.

Start Date01 May 2021

Sponsor / Collaborator

Industria Quimica Farmaceutica Nacional SA.

NCT04292197 / CompletedPhase 1

A Phase 1, Double-Blind, Randomized, Placebo-Controlled, Single/Multiple Day Dose Study to Assess the Safety, Tolerability, and Pharmacokinetics of 18- Methoxycoronaridine (18-MC HCl) Administered Orally to Normal Healthy Volunteers

The primary objective of this study is to assess the safety and tolerability of a single day dosing and a separate multiple day dosing of 18-MC HCl administered orally, each part of the study having a different set of healthy male and female volunteers.

Start Date14 Apr 2020

Sponsor / Collaborator

Mind Medicine (MindMed), Inc.

100 Clinical Results associated with nAChRα3&β4

100 Translational Medicine associated with nAChRα3&β4

0 Patents (Medical) associated with nAChRα3&β4

261

Literatures (Medical) associated with nAChRα3&β4

01 Nov 2024·International Journal of Biological Macromolecules

The α3β4 nAChR tissue distribution identified by fluorescent α-conotoxin [D11A]LvIA

Article

Author: Yu, Jinpeng ; Wang, Meiting ; Luo, Sulan ; Zhu, Xiaopeng ; Xu, Chenxing ; Zhangsun, Dongting ; Wang, Nan ; Pei, Shengrong ; Ma, Tao

α3β4, a vital subtype of neuronal nicotinic acetylcholine receptors (nAChRs), is widely distributed in the brain, ganglia, and adrenal glands, associated with addiction and neurological diseases. However, the lack of specific imaging tools for α3β4 nAChRs has hindered the investigation of their tissue distribution and functions. [D11A]LvIA, a peptide derived from marine cone snails, demonstrates high affinity and potency for α3β4 nAChRs, making it a valuable pharmacological tool for studying this receptor subtype. In this study, three fluorescent conjugates of [D11A]LvIA were synthesized using 6-TAMRA-SE (R), Cy3-NHS-ester (Cy3), and BODIPY-FL NHS ester (BDP) dyes. The electrophysiological activities were assessed in Xenopus laevis oocytes by two-electrodes voltage clamp (TEVC). [D11A]LvIA-Cy3 and [D11A]LvIA-BDP show improved selectivity and affinity, with IC₅₀ values of 512.70 nM and 343.50 nM, respectively, and [D11A]LvIA-Cy3 exhibits better stability in cerebrospinal fluid (CSF). Utilizing [D11A]LvIA-Cy3, we successfully visualized the distribution of α3β4 nAChRs in rat trigeminal ganglia, retina, adrenal glands, and various brain regions. This novel fluorescent peptide provides a significant pharmacological tool for the exploration and visualization in-situ distribution of α3β4 nAChRs in different tissues and also assists in clarifying the function.

01 May 2024·ACS Chemical Neuroscience

Catharanthine Modulates Mesolimbic Dopamine Transmission and Nicotine Psychomotor Effects via Inhibition of α6-Nicotinic Receptors and Dopamine Transporters

Article

Author: Yorgason, Jordan T. ; Arias, Hugo R. ; Kim, Oc-Hee ; Williams, Benjamin M. ; Moedl, Aubrey A. ; McIntosh, J. Michael ; Woolley, Joel T. ; Steed, Nathan D. ; Jang, Eun Young ; Burris, Matthew D. ; Nelson, Christina A. ; Jones, Gavin C. ; Hone, Arik J. ; Steffensen, Scott C.

Iboga alkaloids, also known as coronaridine congeners, have shown promise in the treatment of alcohol and opioid use disorders. The objective of this study was to evaluate the effects of catharanthine and 18-methoxycoronaridine (18-MC) on dopamine (DA) transmission and cholinergic interneurons in the mesolimbic DA system, nicotine-induced locomotor activity, and nicotine-taking behavior. Utilizing ex vivo fast-scan cyclic voltammetry (FSCV) in the nucleus accumbens core of male mice, we found that catharanthine or 18-MC differentially inhibited evoked DA release. Catharanthine inhibition of evoked DA release was significantly reduced by both α4 and α6 nicotinic acetylcholine receptors (nAChRs) antagonists. Additionally, catharanthine substantially increased DA release more than vehicle during high-frequency stimulation, although less potently than an α4 nAChR antagonist, which confirms previous work with nAChR antagonists. Interestingly, while catharanthine slowed DA reuptake measured via FSCV ex vivo, it also increased extracellular DA in striatal dialysate from anesthetized mice in vivo in a dose-dependent manner. Superfusion of catharanthine or 18-MC inhibited the firing rate of striatal cholinergic interneurons in a concentration dependent manner, which are known to potently modulate presynaptic DA release. Catharanthine or 18-MC suppressed acetylcholine currents in oocytes expressing recombinant rat α6/α3β2β3 or α6/α3β4 nAChRs. In behavioral experiments using male Sprague-Dawley rats, systemic administration of catharanthine or 18-MC blocked nicotine enhancement of locomotor activity. Importantly, catharanthine attenuated nicotine self-administration in a dose-dependent manner while having no effect on food reinforcement. Lastly, administration of catharanthine and nicotine together greatly increased head twitch responses, indicating a potential synergistic hallucinogenic effect. These findings demonstrate that catharanthine and 18-MC have similar, but not identical effects on striatal DA dynamics, striatal cholinergic interneuron activity and nicotine psychomotor effects.

11 Jan 2024·Journal of Medicinal ChemistryQ1 · MEDICINE

Synthesis of α3β4 Nicotinic Acetylcholine Receptor Modulators Derived from Aristoquinoline That Reduce Reinstatement of Cocaine-Seeking Behavior

Q1 · MEDICINE

Article

Author: Kulkarni, Gauri C. ; Rusali, Lisa E. ; Argade, Malaika D. ; Gour, Abhishek ; Kremiller, Kyle M. ; Riley, Andrew P. ; Cippitelli, Andrea ; Toll, Lawrence ; Straub, Carolyn J. ; Peters, Christian J. ; Sharma, Abhisheak ; Lopez-Hernandez, Ana M.

Growing evidence suggests that inhibition of the α3β4 nicotinic acetylcholine receptor (nAChR) represents a promising therapeutic strategy to treat cocaine use disorder. Recently, aristoquinoline (1), an alkaloid from Aristotelia chilensis, was identified as an α3β4-selective nAChR inhibitor. Here, we prepared 22 derivatives of 1 and evaluated their ability to inhibit the α3β4 nAChR. These studies revealed structure-activity trends and several compounds with increased potency compared to 1 with few off-target liabilities. Additional mechanistic studies indicated that these compounds inhibit the α3β4 nAChR noncompetitively, but do not act as channel blockers, suggesting they are negative allosteric modulators. Finally, using a cocaine-primed reinstatement paradigm, we demonstrated that 1 significantly attenuates drug-seeking behavior in an animal model of cocaine relapse. The results from these studies further support a role for the α3β4 nAChR in the addictive properties of cocaine and highlight the possible utility of aristoquinoline derivatives in treating cocaine use disorder.

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