JJC8-091 is an atypical

dopamine reuptake inhibitor A dopamine reuptake inhibitor (DRI) is a class of drug which acts as a reuptake inhibitor of the monoamine neurotransmitter dopamine by blocking the action of the dopamine transporter (DAT). Reuptake inhibition is achieved when extracellular dop ...

(DRI) that was derived from

modafinil Modafinil, sold under the brand name Provigil among others, is a central nervous system (CNS) stimulant and wakefulness-promoting agent, eugeroic (wakefulness promoter) medication used primarily to treat narcolepsy, a sleep disorder characteri ...

. It is a lead

compound Compound may refer to: Architecture and built environments * Compound (enclosure), a cluster of buildings having a shared purpose, usually inside a fence or wall ** Compound (fortification), a version of the above fortified with defensive struc ...

for potential treatment of psychostimulant use disorder (PSUD) and is under development by Encepheal Therapeutics for use as a

pharmaceutical drug Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy ( pharmacotherapy) is an important part of the ...

. The

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Pa ...

(K_i) of JJC8-091 for the

dopamine transporter The dopamine transporter (DAT, also sodium-dependent dopamine transporter) is a membrane-spanning protein coded for in humans by the ''SLC6A3'' gene (also known as ''DAT1''), that pumps the neurotransmitter dopamine out of the synaptic cleft ba ...

(DAT) is 230 to 289nM. In another study however, its affinities for the

monoamine transporter Monoamine transporters (MATs) are proteins that function as integral Cell membrane, plasma-membrane Neurotransmitter transporter, transporters to regulate concentrations of extracellular monoamine neurotransmitters. The three major classes are se ...

s were 16.7nM for the DAT, 17,800nM for the

norepinephrine transporter The norepinephrine transporter (NET), also known as noradrenaline transporter (NAT), is a protein that in humans is encoded by the solute carrier family 6 member 2 (SLC6A2) gene. NET is a monoamine transporter and is responsible for the sodium ...

(NET) (1,066-fold lower than for the DAT), and 1,770nM for the

serotonin transporter The serotonin transporter (SERT or 5-HTT) also known as the sodium-dependent serotonin transporter and solute carrier family 6 member 4 is a protein that in humans is encoded by the SLC6A4 gene. SERT is a type of monoamine transporter protein t ...

(SERT) (106-fold lower than for the DAT). It has substantially higher affinity for the DAT than modafinil (K_i = 2,600–8,160nM). Besides the DAT, JJC8-091 is a

sigma Sigma ( ; uppercase Σ, lowercase σ, lowercase in word-final position ς; ) is the eighteenth letter of the Greek alphabet. In the system of Greek numerals, it has a value of 200. In general mathematics, uppercase Σ is used as an operator ...

σ₁ receptor

ligand In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's el ...

(K_i = 454–1,010nM; 2.0–3.5-fold lower than for the DAT). It also has high affinity for the

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...

D₂ and D₃ receptors and lower affinity for the dopamine D₄ receptor (K_i = 298nM, 480nM, and 3,820nM, respectively). JJC8-091 results in a mild, slow-onset, long-duration increase in

levels in the

nucleus accumbens The nucleus accumbens (NAc or NAcc; also known as the accumbens nucleus, or formerly as the ''nucleus accumbens septi'', Latin for ' nucleus adjacent to the septum') is a region in the basal forebrain rostral to the preoptic area of the hypo ...

in animals. The increases in nucleus accumbens dopamine levels with JJC8-091 are blunted relative to those with

cocaine Cocaine is a tropane alkaloid and central nervous system stimulant, derived primarily from the leaves of two South American coca plants, ''Erythroxylum coca'' and ''Erythroxylum novogranatense, E. novogranatense'', which are cultivated a ...

and

JJC8-088 JJC8-088 is a dopamine reuptake inhibitor (DRI) that was chemical derivative, derived from the wakefulness-promoting agent modafinil. It has substantially higher affinity (pharmacology), affinity for the dopamine transporter (DAT) than modafinil ...

(a cocaine-like DRI) but are greater than those of JJC8-016 (an atypical DRI). JJC8-091 does not increase

locomotor activity Locomotor activity is a measure of animal behavior which is employed in scientific research. Hyperlocomotion, also known as locomotor hyperactivity, hyperactivity, or increased locomotor activity, is an effect of certain drugs in animals in whi ...

in animals, is not self-administered, and does not substitute for cocaine, suggesting very low

addictive potential Addiction is a neuropsychological disorder characterized by a persistent and intense urge to use a drug or engage in a behavior that produces natural reward, despite substantial harm and other negative consequences. Repetitive drug use can a ...

. Additionally, it reduces cocaine and

methamphetamine Methamphetamine (contracted from ) is a potent central nervous system (CNS) stimulant that is mainly used as a recreational drug use, recreational or Performance-enhancing substance, performance-enhancing drug and less commonly as a secon ...

self-administration, decreases escalation of methamphetamine intake, and blocks cocaine-induced reinstatement of drug-seeking behaviors. Unlike analogues including JJC8-088,

JJC8-089 JJC8-089 is a dopamine reuptake inhibitor (DRI) that was chemical derivative, derived from modafinil and is related to JJC8-016, JJC8-088, and JJC8-091. Its affinity (pharmacology), affinity (Ki) for the dopamine transporter (DAT) is 37.8nM, for ...

, and RDS03-94, JJC8-091 did not show pro-motivational effects in animals. JJC8-091 was first described in the

scientific literature Scientific literature encompasses a vast body of academic papers that spans various disciplines within the natural and social sciences. It primarily consists of academic papers that present original empirical research and theoretical ...

by 2016. It shows a favorable predicted

drug A drug is any chemical substance other than a nutrient or an essential dietary ingredient, which, when administered to a living organism, produces a biological effect. Consumption of drugs can be via insufflation (medicine), inhalation, drug i ...

-like profile in terms of

metabolism Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...

and

pharmacokinetics Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to describing how the body affects a specific su ...

. However, JJC8-091, similarly to analogues like JJC8-016, has been found to exert

hERG hERG (the human '' Ether-à-go-go''-Related Gene) is a gene () that codes for a protein known as Kv11.1, the alpha subunit of a potassium ion channel. This ion channel (sometimes simply denoted as 'hERG') is best known for its contribution t ...

inhibition Inhibitor or inhibition may refer to: Biology * Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity * Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotransm ...

. In any case, modafinil and novel analogues like JJC8-091 are of interest in the potential treatment of PSUD.

References

{{Ion channel modulators Dopamine reuptake inhibitors Piperazines 4-Fluorophenyl compounds Sulfoxides Secondary alcohols Modafinil analogues

See also

References