Evaluation of Safety, Pharmacokinetic, and Pharmacodynamic Characteristics of a Novel Dual mGluR5/5-HT2AR Antagonist (VVZ-2471) in a Randomized, Double-Blind, First-in-Human Study

Kilmer B, Midgette G, Saloga C. Back in the national spotlight: an assessment of recent changes in drug use and drug policies in the United States. Washington DC: Brookings Institute; 2015.

Google Scholar 

World Health Organization. Global status report on alcohol and health and treatment of substance use disorders. Alcohol Drugs Addict Behav (ADA). 2024. https://www.who.int/publications/i/item/9789240096745. Accessed 11 Mar 2025.

Schuckit MA. Treatment of opioid-use disorders. N Engl J Med. 2016;375(4):357–68.

Article  PubMed  Google Scholar 

Bubar MJ, Cunningham KA. Prospects for serotonin 5-HT2R pharmacotherapy in psychostimulant abuse. Prog Brain Res. 2008;172:319–46.

Article  CAS  PubMed  Google Scholar 

Cleva RM, Watterson LR, Johnson MA, Olive MF. Differential modulation of thresholds for intracranial self-stimulation by mGlu5 positive and negative allosteric modulators: implications for effects on drug self-administration. Front Pharmacol. 2012;2:93.

Article  PubMed  PubMed Central  Google Scholar 

Pehek EA, Nocjar C, Roth BL, Byrd TA, Mabrouk OS. Evidence for the preferential involvement of 5-HT2A serotonin receptors in stress- and drug-induced dopamine release in the rat medial prefrontal cortex. Neuropsychopharmacology. 2006;31(2):265–77.

Article  CAS  PubMed  Google Scholar 

Bortolozzi A, Díaz-Mataix L, Scorza MC, Celada P, Artigas F. The activation of 5-HT receptors in prefrontal cortex enhances dopaminergic activity. J Neurochem. 2005;95(6):1597–607.

Article  CAS  PubMed  Google Scholar 

Porras G, Di Matteo V, Fracasso C, Lucas G, De Deurwaerdère P, Caccia S, et al. 5-HT2A and 5-HT2C/2B receptor subtypes modulate dopamine release induced in vivo by amphetamine and morphine in both the rat nucleus accumbens and striatum. Neuropsychopharmacology. 2002;26(3):311–24.

Article  CAS  PubMed  Google Scholar 

Fletcher PJ, Grottick AJ, Higgins GA. Differential effects of the 5-HT(2A) receptor antagonist M100907 and the 5-HT(2C) receptor antagonist SB242084 on cocaine-induced locomotor activity, cocaine self-administration and cocaine-induced reinstatement of responding. Neuropsychopharmacology. 2002;27(4):576–86.

CAS  PubMed  Google Scholar 

Fletcher PJ, Korth KM, Robinson SR, Baker GB. Multiple 5-HT receptors are involved in the effects of acute MDMA treatment: studies on locomotor activity and responding for conditioned reinforcement. Psychopharmacology. 2002;162(3):282–91.

Article  CAS  PubMed  Google Scholar 

Filip M, Bubar MJ, Cunningham KA. Contribution of serotonin (5-hydroxytryptamine; 5-HT) 5-HT2 receptor subtypes to the hyperlocomotor effects of cocaine: acute and chronic pharmacological analyses. J Pharmacol Exp Ther. 2004;310(3):1246–54.

Article  CAS  PubMed  Google Scholar 

Cunningham KA, Anastasio NC, Fox RG, Stutz SJ, Bubar MJ, Swinford SE, et al. Synergism between a serotonin 5-HT2A receptor (5-HT2AR) antagonist and 5-HT2CR agonist suggests new pharmacotherapeutics for cocaine addiction. ACS Chem Neurosci. 2013;4(1):110–21.

Article  CAS  PubMed  Google Scholar 

McMahon LR, Cunningham KA. Role of 5-HT(2a) and 5-HT(2B/2C) receptors in the behavioral interactions between serotonin and catecholamine reuptake inhibitors. Neuropsychopharmacology. 2001;24(3):319–29.

Article  CAS  PubMed  Google Scholar 

Kalivas PW. The glutamate homeostasis hypothesis of addiction. Nat Rev Neurosci. 2009;10(8):561–72.

Article  CAS  PubMed  Google Scholar 

Olive MF, McGeehan AJ, Kinder JR, McMahon T, Hodge CW, Janak PH, et al. The mGluR5 antagonist 6-methyl-2-(phenylethynyl)pyridine decreases ethanol consumption via a protein kinase C epsilon-dependent mechanism. Mol Pharmacol. 2005;67(2):349–55.

Article  CAS  PubMed  Google Scholar 

Lou ZZ, Chen LH, Liu HF, Ruan LM, Zhou WH. Blockade of mGluR5 in the nucleus accumbens shell but not core attenuates heroin seeking behavior in rats. Acta Pharmacol Sin. 2014;35(12):1485–92.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Vendruscolo LF, Vendruscolo JCM, Whiting KE, Acri JB, Volkow ND, Koob GF. The mGlu5 receptor negative allosteric modulator mavoglurant reduces escalated cocaine self-administration in male and female rats. Psychopharmacology. 2024;241(11):2303–13.

Article  CAS  PubMed  PubMed Central  Google Scholar 

U.S. Food and Drug Administration. Guidance for industry: estimating the maximum safe starting dose in adult healthy volunteer. 2005.

Beck AT, Steer RA, Brown G. Beck depression inventory—II. Psychological assessment. 1996.

Cox LS, Tiffany ST, Christen AG. Evaluation of the brief questionnaire of smoking urges (QSU-brief) in laboratory and clinical settings. Nicotine Tob Res. 2001;3(1):7–16.

Article  CAS  PubMed  Google Scholar 

Riaza Bermudo-Soriano C, Perez-Rodriguez MM, Vaquero-Lorenzo C, Baca-Garcia E. New perspectives in glutamate and anxiety. Pharmacol Biochem Behav. 2012;100(4):752–74.

Article  CAS  PubMed  Google Scholar 

Blackshaw LA, Page AJ, Young RL. Metabotropic glutamate receptors as novel therapeutic targets on visceral sensory pathways. Front Neurosci. 2011;5:40.

Article  PubMed  PubMed Central  Google Scholar 

Kalliomäki J, Huizar K, Kågedal M, Hägglöf B, Schmelz M. Evaluation of the effects of a metabotropic glutamate receptor 5-antagonist on electrically induced pain and central sensitization in healthy human volunteers. Eur J Pain. 2013;17(10):1465–71.

Article  PubMed  Google Scholar 

Rohof WO, Lei A, Hirsch DP, Ny L, Astrand M, Hansen MB, et al. The effects of a novel metabotropic glutamate receptor 5 antagonist (AZD2066) on transient lower oesophageal sphincter relaxations and reflux episodes in healthy volunteers. Aliment Pharmacol Ther. 2012;35(10):1231–42.

Article  CAS  PubMed  Google Scholar 

Zerbib F, Bruley des Varannes S, Roman S, Tutuian R, Galmiche JP, Mion F, et al. Randomised clinical trial: effects of monotherapy with ADX10059, a mGluR5 inhibitor, on symptoms and reflux events in patients with gastro-oesophageal reflux disease. Aliment Pharmacol Ther. 2011;33(8):911–21.

Article  CAS  PubMed  Google Scholar 

Bousman CA, Stevenson JM, Ramsey LB, Sangkuhl K, Hicks JK, Strawn JR, et al. Clinical pharmacogenetics implementation consortium (CPIC) guideline for CYP2D6, CYP2C19, CYP2B6, SLC6A4, and HTR2A genotypes and serotonin reuptake inhibitor antidepressants. Clin Pharmacol Ther. 2023;114(1):51–68.

Article  CAS  PubMed  Google Scholar 

Yingst JM, Lester C, Livelsberger C, Allen SI, Hammett E, Veldheer S, et al. Pilot randomized controlled trial evaluating the effect of random nicotine delivery on cigarettes per day and smoke exposure. Brain Res Bull. 2022;1(188):30–7.

Article  Google Scholar 

Jeon DW, Shim JC, Kong BG, Moon JJ, Seo YS, Kim SJ, et al. Adjunctive varenicline treatment for smoking reduction in patients with schizophrenia: a randomized double-blind placebo-controlled trial. Schizophr Res. 2016;176(2–3):206–11.

Article  PubMed  Google Scholar 

Espinoza-Fonseca LM. The benefits of the multi-target approach in drug design and discovery. Bioorg Med Chem. 2006;14(4):896–7.

Article  CAS  PubMed  Google Scholar 

Talevi A. Multi-target pharmacology: possibilities and limitations of the “skeleton key approach” from a medicinal chemist perspective. Front Pharmacol. 2015;6:205.

Article  PubMed  PubMed Central  Google Scholar 

Ramsay RR, Popovic-Nikolic MR, Nikolic K, Uliassi E, Bolognesi ML. A perspective on multi-target drug discovery and design for complex diseases. Clin Transl Med. 2018;7(1):3.

Article  PubMed  PubMed Central  Google Scholar 

Pang MH, Kim Y, Jung KW, Cho S, Lee DH. A series of case studies: practical methodology for identifying antinociceptive multi-target drugs. Drug Discov Today. 2012;17(9–10):425–34.

Article  CAS  PubMed  Google Scholar 

Song I, Cho S, Nedeljkovic SS, Lee SR, Lee C, Kim J, et al. Role of VVZ-149, a novel analgesic molecule, in the affective component of pain: results from an exploratory proof-of-concept study of postoperative pain following laparoscopic and robotic-laparoscopic gastrectomy. Pain Med. 2021;22(9):2037–49.

Article  PubMed  Google Scholar 

Nedeljkovic SS, Song I,

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