RO5073012 is a selective low-

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 ...

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

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 has been 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 ...

. TAAR1 partial agonists like RO5073012 can have

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 ...

- 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.

Pharmacology

Pharmacodynamics

Actions

RO5073012 has 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 mouse, rat,

cynomolgus monkey The crab-eating macaque (''Macaca fascicularis''), also known as the long-tailed macaque or cynomolgus macaque, is a cercopithecine primate native to Southeast Asia. As a synanthropic species, the crab-eating macaque thrives near human settlem ...

, and human TAAR1 (K_i = 0.5–6nM), is highly potent and selective as an agonist of the TAAR1 of these species ( = 8.8–25nM), and has relatively low

intrinsic activity Intrinsic activity (IA) and efficacy (Emax) refer to the relative ability of a drug- receptor complex to produce a maximum functional response. This must be distinguished from the affinity, which is a measure of the ability of the drug to bind ...

at the TAAR1 of these species ( = 24–43% relative to

β-phenethylamine Phenethylamine (PEA) is an organic compound, natural monoamine alkaloid, and trace amine, which acts as a central nervous system stimulant in humans. In the brain, phenethylamine regulates monoamine neurotransmission by binding to trace ami ...

Effects

RO5073012 by itself has no effect on

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 normal mice. It dose-dependently suppresses

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 ...

-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 ...

psychostimulant Stimulants (also known as central nervous system stimulants, or psychostimulants, or colloquially as uppers) are a class of drugs that increase alertness. They are used for various purposes, such as enhancing attention, motivation, cognition ...

-like effect) in rats, with near-complete suppression of cocaine-induced locomotor stimulation at the highest dose of RO5073012. Other TAAR1 agonists, including both partial agonists and

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 ...

s, likewise suppress psychostimulant-induced hyperlocomotion. Conversely however, and in contrast to other TAAR1 partial agonists, RO5073012 non-significantly reduced the locomotor activity induced by

amphetamine Amphetamine (contracted from Alpha and beta carbon, alpha-methylphenethylamine, methylphenethylamine) is a central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, an ...

in normal mice. The reasons for this difference from other TAAR1 partial agonists are unclear, though RO5073012 has notably lower TAAR1 efficacy than other TAAR1 partial agonists. RO5073012 reduces basal locomotor activity in

transgenic A transgene is a gene that has been transferred naturally, or by any of a number of genetic engineering techniques, from one organism to another. The introduction of a transgene, in a process known as transgenesis, has the potential to change the ...

mice with TAAR1 overexpression.

Amphetamine Amphetamine (contracted from Alpha and beta carbon, alpha-methylphenethylamine, methylphenethylamine) is a central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, an ...

produces only weak locomotor stimulation in mice with TAAR1 overexpression, and RO5073012, by antagonizing the TAAR1, has been found to restore

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 in this context.

Pharmacokinetics

The drug has favorable

physicochemical Physical chemistry is the study of macroscopic and microscopic phenomena in chemical systems in terms of the principles, practices, and concepts of physics such as motion, energy, force, time, thermodynamics, quantum chemistry, statistical mecha ...

and

pharmacokinetic 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 subs ...

properties for use ''

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 ...

''.

History

RO5073012 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 2012. It has been relatively little-studied compared to other TAAR1 partial agonists, for instance RO5166017, RO5203648, and RO5263397.

References

{{TAAR ligands Anilines 4-Chlorophenyl compounds Imidazoles TAAR1 agonists TAAR1 antagonists Isopropylamino compounds