JDTic is a selective, long-acting ("inactivating") antagonist of the

κ-opioid receptor The κ-opioid receptor or kappa opioid receptor, abbreviated KOR or KOP, is a G protein-coupled receptor that in humans is encoded by the ''OPRK1'' gene. The KOR is coupled to the G protein Gi/G0 and is one of four related receptors that bind op ...

(KOR). JDTic is a 4-phenylpiperidine derivative, distantly related structurally to analgesics such as

pethidine Pethidine, also known as meperidine and sold under the brand name Demerol among others, is a synthetic opioid pain medication of the phenylpiperidine class. Synthesized in 1938 as a potential anticholinergic agent by the German chemist Otto Eis ...

and

ketobemidone Ketobemidone, sold under the brand name Ketogan among others, is a powerful synthetic opioid painkiller. Its effectiveness against pain is in the same range as morphine, and it also has some NMDA-antagonist properties imparted, in part, by its m ...

, and more closely to the MOR antagonist alvimopan. In addition, it is structurally distinct from other KOR antagonists such as norbinaltorphimine. JDTic has been used to create

crystal structures A crystal or crystalline solid is a solid material whose constituents (such as atoms, molecules, or ions) are arranged in a highly ordered microscopic structure, forming a crystal lattice that extends in all directions. In addition, macrosc ...

of KOR

Pharmacology

JDTic is a long-acting ("inactivating") antagonist of the KOR, and is reported to be highly selective for the KOR over the

μ-opioid receptor The μ-opioid receptors (MOR) are a class of opioid receptors with a high affinity for enkephalins and beta-endorphin, but a low affinity for dynorphins. They are also referred to as μ(''mu'')-opioid peptide (MOP) receptors. The prototypical � ...

(MOR),

δ-opioid receptor The δ-opioid receptor, also known as delta opioid receptor or simply delta receptor, abbreviated DOR or DOP, is an inhibitory 7-transmembrane G-protein coupled receptor coupled to the G protein Gi/G0 and has enkephalins as its endogenous lig ...

(DOR), and

nociceptin receptor The nociceptin opioid peptide receptor (NOP), also known as the nociceptin/orphanin FQ (N/OFQ) receptor or kappa-type 3 opioid receptor, is a protein that in humans is encoded by the ''OPRL1'' (opioid receptor-like 1) gene. The nociceptin receptor ...

(NOP). However, in another study, JDTic showed little selectivity over the μ-opioid receptor, though it failed to block the effects of the selective μ-opioid receptor agonist

sufentanil Sufentanil, sold under the brand names Dsuvia and Sufenta, is a synthetic opioid analgesic drug approximately 5 to 10 times as potent as its parent drug, fentanyl, and 500 times as potent as morphine. Structurally, sufentanil differs from fen ...

across a wide range of doses in animals. It has a very long duration of action, with effects in animals seen for up to several weeks after administration of a single dose, although its binding to the KOR is not technically "irreversible" and its long-acting effects are instead caused by altered activity of c-Jun N-terminal kinases. Animal studies suggest that JDTic may produce antidepressant,

anxiolytic An anxiolytic (; also antipanic or antianxiety agent) is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxiet ...

, and anti-stress effects, as well as having possible application in the treatment of

addiction Addiction is a neuropsychological disorder characterized by a persistent and intense urge to engage in certain behaviors, one of which is the usage of a drug, despite substantial harm and other negative consequences. Repetitive drug use o ...

cocaine Cocaine (from , from , ultimately from Quechua: ''kúka'') is a central nervous system (CNS) stimulant mainly used recreationally for its euphoric effects. It is primarily obtained from the leaves of two Coca species native to South Ameri ...

and

morphine Morphine is a strong opiate that is found naturally in opium, a dark brown resin in poppies (''Papaver somniferum''). It is mainly used as a pain medication, and is also commonly used recreationally, or to make other illicit opioids. T ...

. JDTic shows robust activity in animal models of depression,

anxiety Anxiety is an emotion which is characterized by an unpleasant state of inner turmoil and includes feelings of dread over anticipated events. Anxiety is different than fear in that the former is defined as the anticipation of a future threat wh ...

stress Stress may refer to: Science and medicine * Stress (biology), an organism's response to a stressor such as an environmental condition * Stress (linguistics), relative emphasis or prominence given to a syllable in a word, or to a word in a phrase ...

-induced

relapse In internal medicine, relapse or recidivism is a recurrence of a past (typically medical) condition. For example, multiple sclerosis and malaria often exhibit peaks of activity and sometimes very long periods of dormancy, followed by relapse or ...

, and

nicotine withdrawal Nicotine withdrawal is a group of symptoms that occur in the first few weeks after stopping or decreasing use of nicotine. Symptoms include intense cravings for nicotine, anger or irritability, anxiety, depression, impatience, trouble sleeping, ...

Discontinuation of clinical development

During phase I

human Humans (''Homo sapiens'') are the most abundant and widespread species of primate, characterized by bipedalism and exceptional cognitive skills due to a large and complex brain. This has enabled the development of advanced tools, cultu ...

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, diet ...

s for the treatment of

cocaine abuse Cocaine dependence is a neurological disorder that is characterized by withdrawal symptoms upon cessation from cocaine use. It also often coincides with cocaine addiction which is a biopsychosocial disorder characterized by persistent use of coc ...

, development of JDTic was halted due to the occurrence of non-sustained ventricular tachycardia, a type of arrhythmia that can potentially be life-threatening. In addition, JDTic showed an unfavorable brain-to-plasma concentration ratio, indicating poor

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...

penetration. As a result, new KOR antagonists with more favorable drug profiles (e.g., short-acting, improved brain penetration, etc.), such as ALKS-5461 (a combination of

buprenorphine Buprenorphine is an opioid used to treat opioid use disorder, acute pain, and chronic pain. It can be used under the tongue (sublingual), in the cheek (buccal), by injection (intravenous and subcutaneous), as a skin patch (transdermal ...

and

samidorphan Samidorphan (, ) (developmental code names ALKS-33, RDC-0313), is an opioid antagonist which in the form of olanzapine/samidorphan (brand name Lybalvi) is used in the treatment of schizophrenia and bipolar disorder. Samidorphan reduces the weight ...

) and CERC-501 (formerly LY-2456302), are being developed instead. The discontinuation of the clinical development of JDTic is detailed in the following important literature quote: In the same paper, LY-2456302 (now CERC-501) was described, "The LY2456302 compound developed by Eli Lilly is an example of a KOR antagonist that does not strongly activate JNK. In a recent phase 1 trial of LY2456302, the authors concluded that the drug was well-tolerated with no clinically significant findings (Lowe et al, 2014)." Note that KOR antagonists that strongly activate JNK are inactivating (long-acting) while those that do not are non-inactivating (short-acting), and that inactivating KOR antagonists are more "complete" and hence potentially more risky inhibitors of the KOR than are non-inactivating antagonists.

References

{{Opioidergics 4-Phenylpiperidines Carboxamides Delta-opioid receptor antagonists Irreversible antagonists Kappa-opioid receptor antagonists Mu-opioid receptor antagonists Phenols Synthetic opioids Tetrahydroisoquinolines

Pharmacology

Discontinuation of clinical development

See also

References