JRT is a serotonin receptor modulator and putative

serotonergic psychedelic Psychedelics are a subclass of hallucinogenic drugs whose primary effect is to trigger non-ordinary mental states (known as psychedelic experiences or "trips") and a perceived "expansion of consciousness". Also referred to as classic halluci ...

and

psychoplastogen Psychoplastogens, also known as neuroplastogens, are a group of Small molecule#Drugs, small molecule drugs that produce rapid and sustained effects on neuronal structure and function, intended to manifest therapeutic benefit after a single admin ...

related to

lysergic acid diethylamide Lysergic acid diethylamide, commonly known as LSD (from German ; often referred to as acid or lucy), is a Semisynthesis, semisynthetic, Hallucinogen, hallucinogenic compound derived from ergot, known for its powerful psychological effects and ...

(LSD). It is the analogue of LSD in which the embedded

tryptamine Tryptamine is an indolamine metabolite of the essential amino acid tryptophan. The chemical structure is defined by an indole—a fused benzene and pyrrole ring, and a 2-aminoethyl group at the second carbon (third aromatic atom, with the firs ...

structure A structure is an arrangement and organization of interrelated elements in a material object or system, or the object or system so organized. Material structures include man-made objects such as buildings and machines and natural objects such as ...

within the

ergoline Ergoline is a core structure in many alkaloids and their synthetic derivatives. Ergoline alkaloids were first characterized in ergot. Some of these are implicated in the condition of ergotism, which can take a convulsive form or a gangrenous for ...

ring system A ring system is a disc or torus orbiting an astronomical object that is composed of solid material such as dust, meteoroids, planetoids, moonlets, or stellar objects. Ring systems are best known as planetary rings, common components of sate ...

of LSD has been replaced with an

isotryptamine Isotryptamine, also known as 2-(1-indolyl)ethylamine, is a chemical compound and positional isomer of tryptamine (2-(3-indolyl)ethylamine). A variety of isotryptamine chemical derivative, derivatives, or chemical substituent, substituted isotrypt ...

structure. It acts as a non-selective serotonin receptor modulator, including as a

partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given Receptor (biochemistry), receptor, but have only partial Intrinsic activity, efficacy at the receptor relative to a full agonist. They may also be considered Ligand (bio ...

of the serotonin 5-HT_2A receptor and as an agonist or

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.serotonin receptor 5-HT receptors, 5-hydroxytryptamine receptors, or serotonin receptors, are a group of G protein-coupled receptor and ligand-gated ion channels found in multiple tissues including the central and peripheral nervous systems. They mediate both ex ...

s. The drug has psychedelic-like, psychoplastogenic,

antipsychotic Antipsychotics, previously known as neuroleptics and major tranquilizers, are a class of Psychiatric medication, psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), p ...

-like,

antidepressant Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction. Common side effects of antidepressants include Xerostomia, dry mouth, weight gain, dizziness, headaches, akathi ...

-like, and pro-cognitive effects in animals and preclinical studies, whilst lacking apparent pro-psychotic-like effects. It has significant but reduced psychedelic-like effects compared to LSD. JRT 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 2022. It was developed by David E. Olson and colleagues in association with Delix Therapeutics. The drug is being investigated as a possible treatment for

schizophrenia Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...

Pharmacology

In contrast to LSD, (+)-JRT is highly selective for a subset of

serotonin receptor 5-HT receptors, 5-hydroxytryptamine receptors, or serotonin receptors, are a group of G protein-coupled receptor and ligand-gated ion channels found in multiple tissues including the central and peripheral nervous systems. They mediate both ex ...

s and does not bind to various

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 ...

adrenergic Adrenergic means "working on adrenaline (epinephrine) or noradrenaline (norepinephrine)" (or on their receptors). When not further qualified, it is usually used in the sense of enhancing or mimicking the effects of epinephrine and norepinephrine ...

, or

histamine receptor The histamine receptors are a class of G protein–coupled receptors which bind histamine as their primary endogenous ligand. Histamine is a neurotransmitter involved in various physiological processes. There are four main types of histamine recep ...

s. (+)-JRT shows high

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 ...

for the

serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...

5-HT₂ receptors, with K_i values ranging from 2.0 to 184nM. It is a potent

of the serotonin 5-HT_2A and 5-HT_2B receptors ( = 33–81% and 48–51%, respectively) and a

full agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the agoni ...

of the serotonin 5-HT_2C receptor ( = 89%). The drug is also an

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

of the serotonin 5-HT_1A and 5-HT₇ receptors, an

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.5-HT_5A and 5-HT₇ receptors, and binds to the serotonin 5-HT₆ receptor. It does not have significant affinity for the serotonin 5-HT_1B or 5-HT₃ receptors, whereas the other serotonin 5-HT₁ receptors and the serotonin 5-HT₄ receptor were not reported. (+)-JRT is 4.4- to 180-fold less potent than LSD as a serotonin 5-HT_2A receptor agonist ''

in vitro ''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...

'' ( = 0.4–90nM vs. 0.09–0.5nM, respectively) and is less

efficacious Efficacy is the ability to perform a task to a satisfactory or expected degree. The word comes from the same roots as ''effectiveness'', and it has often been used synonymously, although in pharmacology a distinction is now often made between ...

than LSD in activating the receptor ( = 33% vs. 44–63%, respectively). (+)-JRT dissociates from the serotonin 5-HT_2A receptor approximately 10-fold more quickly than LSD. (+)-JRT produces the

head-twitch response The head-twitch response (HTR), also sometimes known as wet dog shakes (WDS) in rats, is a rapid side-to-side head movement that occurs in mice and rats in association with serotonin 5-HT2A receptor activation. Serotonergic psychedelics like lys ...

(HTR), a behavioral proxy of

psychedelic Psychedelics are a subclass of hallucinogenic drugs whose primary effect is to trigger non-ordinary mental states (known as psychedelic experiences or "trips") and a perceived "expansion of consciousness". Also referred to as classic halluci ...

effects, in rodents, and hence would be expected to be

hallucinogen Hallucinogens, also known as psychedelics, entheogens, or historically as psychotomimetics, are a large and diverse class of psychoactive drugs that can produce altered states of consciousness characterized by major alterations in thought, mo ...

ic in humans. However, the drug shows a reduced HTR compared to LSD, producing less than half the maximal number of head twitches. It can also antagonize the HTR induced by LSD. Hence, (+)-JRT may be less psychedelic than LSD in humans. LSD and (+)-JRT are of similar

potency Potency may refer to: * Potency (pharmacology), a measure of the activity of a drug in a biological system * Virility * Cell potency, a measure of the differentiation potential of stem cells * In homeopathic dilutions, potency is a measure of ho ...

in this effect, with maximal HTR being achieved at 0.2mg/kg for both compounds. (+)-JRT does not affect

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 ...

and does not produce any serotonin behavioral syndrome-type effects. It has been found to inhibit

dextroamphetamine Dextroamphetamine (international nonproprietary name, INN: dexamfetamine) is a potent central nervous system (CNS) stimulant and enantiomer of amphetamine that is used in the treatment of attention deficit hyperactivity disorder (ADHD) and narc ...

-induced

hyperlocomotion 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 female but not male mice, does not exacerbate

phencyclidine Phencyclidine or phenylcyclohexyl piperidine (PCP), also known in its use as a street drug as angel dust among other names, is a dissociative anesthetic mainly used recreationally for its significant mind-altering effects. PCP may cause hall ...

(PCP)-induced hyperlocomotion, does not worsen dizocilpine (MK-801)-induced

prepulse inhibition Prepulse inhibition (PPI) is a neurological phenomenon in which a weaker prestimulus (prepulse) inhibits the reaction of an organism to a subsequent strong reflex-eliciting stimulus (pulse), often using the startle reflex. The stimuli are usually ...

(PPI), and does not induce PPI deficits itself. Some of these findings are in contrast to LSD, and are suggestive that (+)-JRT lacks

psychotic In psychopathology, psychosis is a condition in which a person is unable to distinguish, in their experience of life, between what is and is not real. Examples of psychotic symptoms are delusions, hallucinations, and disorganized or incoher ...

-like effects and may have

potential. In addition to the preceding findings, (+)-JRT has been reported to increase

neuroplasticity Neuroplasticity, also known as neural plasticity or just plasticity, is the ability of neural networks in the brain to change through neurogenesis, growth and reorganization. Neuroplasticity refers to the brain's ability to reorganize and rewir ...

and hence to act as a

, to produce

-like effects, and to promote

cognitive flexibility Cognitive flexibility is an intrinsic property of a cognitive system often associated with the mental ability to adjust its activity and content, switch between different task rules and corresponding behavioral responses, maintain multiple con ...

. It was equivalent with LSD in terms of psychoplastogenic effects.

Chemistry

JRT is the analogue of the

lysergamide Lysergamides, also known as ergoamides or as lysergic acid amides, are amides of lysergic acid (LA). They are ergolines, with some lysergamides being found naturally in ergot as well as other fungi. Lysergamides are notable in containing embedd ...

(LSD) in which the embedded

within the

of LSD has been replaced with an

structure. Hence, JRT is not an ergoline, lysergamide, or tryptamine itself, but could be considered a cyclized isotryptamine. JRT exists as four

enantiomer In chemistry, an enantiomer (Help:IPA/English, /ɪˈnænti.əmər, ɛ-, -oʊ-/ Help:Pronunciation respelling key, ''ih-NAN-tee-ə-mər''), also known as an optical isomer, antipode, or optical antipode, is one of a pair of molecular entities whi ...

s, including (+)-JRT and (–)-JRT, with (+)-JRT being the active enantiomer.

History

JRT was developed by Jeremy R. Tuck (J.R.T.), Lee E. Dunlap, David E. Olson, and other colleagues at Delix Therapeutics and the

University of California, Davis The University of California, Davis (UC Davis, UCD, or Davis) is a Public university, public Land-grant university, land-grant research university in Davis, California, United States. It is the northernmost of the ten campuses of the University ...

. It was first described in the

by 2022.

Research

JRT is being investigated as a possible treatment for

References

External links