RTI-7470-44 is a potent and selective

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.trace amine-associated receptor 1 Trace amine-associated receptor 1 (TAAR1) is a trace amine-associated receptor (TAAR) protein that in humans is encoded by the ''TAAR1'' gene. TAAR1 is a primarily intracellular amine-activated and G protein-coupled receptor (GPCR) that is p ...

(TAAR1) which is used in

scientific research The scientific method is an empirical method for acquiring knowledge that has been referred to while doing science since at least the 17th century. Historically, it was developed through the centuries from the ancient and medieval world. The ...

. It was discovered in 2022 and is the first potent antagonist of the human TAAR1 to be identified, following the potent mouse TAAR1

inverse agonist In pharmacology, an inverse agonist is a drug that binds to the same receptor as an agonist but induces a pharmacological response opposite to that of the agonist. A neutral antagonist has no activity in the absence of an agonist or inverse agon ...

EPPTB in 2009.

Pharmacology

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 RTI-7470-44 for the human TAAR1 is 0.3nM and its inhibitory potency () at the receptor is 8.4nM ''

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 ...

''. It is about 90-fold less potent at the rat TAAR1 ( = 748nM) and 140-fold less potent at the mouse TAAR1 ( = 1,190nM) compared to the human TAAR1. Surprisingly, RTI-7470-44 was found to be a

competitive antagonist A receptor antagonist is a type of receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. Antagonist drugs interfere in the natural operation of recep ...

of the human and mouse TAAR1 but a

non-competitive antagonist A receptor antagonist is a type of Receptor (biochemistry), receptor ligand (biochemistry), ligand or drug that blocks or dampens a biological response by binding to and blocking a Receptor (biochemistry), receptor rather than activating it like ...

of the rat TAAR1. The compound has favorable ''

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, an ...

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 properties, including good

blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that regulates the transfer of solutes and chemicals between the circulatory system and the central nervous system ...

permeability, moderate

metabolic stability Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. More generally, xenobiotic metabolism (from the Greek xenos "stranger" and biotic "related to living beings") is the set of ...

, and a favorable preliminary profile of

off-target activity Off-target activity is biological activity of a drug that is different from and not at that of its intended biological target. It most commonly contributes to side effects. However, in some cases, off-target activity can be taken advantage of for t ...

(≥1–10μM at 42other targets). It is far more potent (893-fold) as an antagonist of the human TAAR1 than the earlier TAAR1 inverse agonist EPPTB ''in vitro'', which has dramatically lower potency (165–272-fold) at the human TAAR1 and rat TAAR1 compared to the mouse TAAR1. RTI-7470-44 has been found to increase the spontaneous

firing rate Rate of fire is the frequency at which a specific weapon can fire or launch its projectiles. This can be influenced by several factors, including operator training level, mechanical limitations, ammunition availability, and weapon condition. In m ...

dopaminergic Dopaminergic means "related to dopamine" (literally, "working on dopamine"), a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain. Dopaminergic pathways, Dopaminergic brain pathways facil ...

neuron A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...

s in mouse

ventral tegmental area The ventral tegmental area (VTA) (tegmentum is Latin for ''covering''), also known as the ventral tegmental area of Tsai, or simply ventral tegmentum, is a group of neurons located close to the midline on the floor of the midbrain. The VTA is th ...

(VTA) slices ''

ex vivo refers to biological studies involving tissues, organs, or cells maintained outside their native organism under controlled laboratory conditions. By carefully managing factors such as temperature, oxygenation, nutrient delivery, and perfusi ...

'' and to block the effects of the high-

efficacy 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 betwee ...

TAAR1

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 ...

RO5166017 RO5166017, or RO-5166017, is a drug developed by Hoffmann-La Roche which acts as a potent and selective agonist for the trace amine-associated receptor 1 (TAAR1), with no significant activity at other targets. It is a partial agonist or near-f ...

in this system.

History

RTI-7470-44 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 ...

in 2022. It was identified via

high throughput screening High-throughput screening (HTS) is a method for scientific discovery especially used in drug discovery and relevant to the fields of biology, materials science and chemistry. Using robotics, data processing/control software, liquid handling device ...

followed by structure–activity optimization.

References

{{TAAR ligands Acetamides 4-Chlorophenyl compounds Experimental drugs Nitriles Pyrimidines Receptor antagonists Sulfur compounds Trifluoromethyl compounds TAAR1 antagonists

Pharmacology

History

See also

References