An Update of Ketamine Illicit Use

Ketamine is a derivative of phencyclidine with unique anesthetic, analgesic, as well as antidepressant pharmacological properties. Despite its clinical use, ketamine is classified on the list with new psychoactive substances having psychedelic properties. The abuse trend of ketamine increasing globally, and it became a common club drug over the past few decades. Of note, recreational use of ketamine may pose a threat to public health, leading to numerous physical, as well as psychiatric negative effects. In addition, simultaneously or sequentially ketamine use with other drugs, resulting in serious health consequences. Currently, there are no specific treatment options for managing compulsive drug-seeking behavior in patients with ketamine use disorder, while the pharmacotherapy of side effects is limited and mostly symptomatic. In this chapter, we discuss ketamine abuse history. Further, we proposed the mechanisms of neural disinhibition underlying addiction development in ketamine-dependent patients. We have also included details of possible negative consequences focusing on long-term and recreational ketamine use for both, central and peripheral systems. Finally, we provide an overview of ketamine concomitant use and corresponding adverse interactions

PK20, a new opioid-neurotensin hybrid peptide that exhibits central and peripheral antinociceptive effects

<p>Abstract</p> <p>Background</p> <p>The clinical treatment of various types of pain relies upon the use of opioid analgesics. However most of them produce, in addition to the analgesic effect, several side effects such as the development of dependence and addiction as well as sedation, dysphoria, and constipation. One solution to these problems are chimeric compounds in which the opioid pharmacophore is hybridized with another type of compound to incease antinociceptive effects. Neurotensin-induced antinociception is not mediated through the opioid system. Therefore, hybridizing neurotensin with opioid elements may result in a potent synergistic antinociceptor.</p> <p>Results</p> <p>Using the known structure-activity relationships of neurotensin we have synthesized a new chimeric opioid-neurotensin compound PK20 which is characterized by a very strong antinociceptive potency. The observation that the opioid antagonist naltrexone did not completely reverse the antinociceptive effect, indicates the partial involvement of the nonopioid component in PK20 in the produced analgesia.</p> <p>Conclusions</p> <p>The opioid-neurotensin hybrid analogue PK20, in which opioid and neurotensin pharmacophores overlap partially, expresses high antinociceptive tail-flick effects after central as well as peripheral applications.</p

In vivo antinociception of potent mu opioid agonist tetrapeptide analogues and comparison with a compact opioid agonist - neurokinin 1 receptor antagonist chimera

<p>Abstract</p> <p>Background</p> <p>An important limiting factor in the development of centrally acting pharmaceuticals is the blood-brain barrier (BBB). Transport of therapeutic peptides through this highly protective physiological barrier remains a challenge for peptide drug delivery into the central nervous system (CNS). Because the most common strategy to treat moderate to severe pain consists of the activation of opioid receptors in the brain, the development of active opioid peptide analogues as potential analgesics requires compounds with a high resistance to enzymatic degradation and an ability to cross the BBB.</p> <p>Results</p> <p>Herein we report that tetrapeptide analogues of the type H-Dmt¹-Xxx²-Yyy³-Gly⁴-NH₂are transported into the brain after intravenous and subcutaneous administration and are able to activate the μ- and δ opioid receptors more efficiently and over longer periods of time than morphine. Using the hot water tail flick test as the animal model for antinociception, a comparison in potency is presented between a side chain conformationally constrained analogue containing the benzazepine ring (BVD03, Yyy³: Aba), and a "ring opened" analogue (BVD02, Yyy³: Phe). The results show that in addition to the increased lipophilicity through amide bond N-methylation, the conformational constraint introduced at the level of the Phe³side chain causes a prolonged antinociception. Further replacement of NMe-D-Ala²by D-Arg²in the tetrapeptide sequence led to an improved potency as demonstrated by a higher and maintained antinociception for AN81 (Xxx²: D-Arg) vs. BVD03 (Xxx²: NMe-D-Ala). A daily injection of the studied opioid ligands over a time period of 5 days did however result in a substantial decrease in antinociception on the fifth day of the experiment. The compact opioid agonist - NK1 antagonist hybrid SBCHM01 could not circumvent opioid induced tolerance.</p> <p>Conclusions</p> <p>We demonstrated that the introduction of a conformational constraint has an important impact on opioid receptor activation and subsequent antinociception in vivo. Further amino acid substitution allowed to identify AN81 as an opioid ligand able to access the CNS and induce antinociception at very low doses (0.1 mg/kg) over a time period up to 7 hours. However, tolerance became apparent after repetitive i.v. administration of the investigated tetrapeptides. This side effect was also observed with the dual opioid agonist-NK1 receptor antagonist SBCHM01.</p

Novel Opioid-Neurotensin-Based Hybrid Peptide with Spinal Long-Lasting Antinociceptive Activity and a Propensity to Delay Tolerance Development

The behavioral responses exerted by spinal administration of the opioid-neurotensin hybrid peptide, PK23, were studied in adult male rats. The antinociceptive effect upon exposure to a thermal stimulus, as well as tolerance development, was assessed in an acute pain model. The PK23 chimera at a dose of 10 nmol/rat produced a potent pain-relieving effect, especially after its intrathecal administration. Compared with intrathecal morphine, this novel compound was found to possess a favourable side effect profile characterized by a reduced scratch reflex, delayed development of analgesic tolerance or an absence of motor impairments when given in the same manner, though some animals died following barrel rotation as a result of its i.c.v. administration (in particular at doses higher than 10 nmol/rat). Nonetheless, these results suggest the potential use of hybrid compounds encompassing both opioid and neurotensin structural fragments in pain management. This highlights the enormous potential of synthetic neurotensin analogues as promising future analgesics

Chimeric Structures in Mental Illnesses—“Magic” Molecules Specified for Complex Disorders

Mental health problems cover a wide spectrum of diseases, including mild to moderate anxiety, depression, alcohol/drug use disorders, as well as bipolar disorder and schizophrenia. Pharmacological treatment seems to be one of the most effective opportunities to recover function efficiently and satisfactorily. However, such disorders are complex as several target points are involved. This results in a necessity to combine different types of drugs to obtain the necessary therapeutic goals. There is a need to develop safer and more effective drugs. Considering that mental illnesses share multifactorial processes, the paradigm of one treatment with multiple modes of action rather than single-target strategies would be more effective for successful therapies. Therefore, hybrid molecules that combine two pharmacophores in one entity show promise, as they possess the desired therapeutic index with a small off-target risk. This review aims to provide information on chimeric structures designed for mental disorder therapy (i.e., schizophrenia and depression), and new types of drug candidates currently being tested. In addition, a discussion on some benefits and limitations of multifunctional, bivalent drug candidates is also given

Antipsychotic Drugs Efficacy in Dextromethorphan-Induced Psychosis

Psychosis is known as a broad term of symptoms that cause serious disorganization of behavior, thinking, and perception of reality. One of the medicines that recently gained much attention in terms of its psychotic potential is dextromethorphan (DXM). DXM, a widely used antitussive drug, is a commonly abused drug because of its euphoric, hallucinogenic, and dissociative properties. To date, DXM is a legally marketed cough suppressant that is neither a controlled substance nor a regulated chemical under the Controlled Substances Act. The management of DXM-related psychosis is dependent on the type of psychotic symptoms. Atypical neuroleptics (i.e., olanzapine, risperidone, quetiapine) and typical haloperidol have been used in symptomatic treatment due to their efficacy, especially in positive symptoms (hallucinations and delusions). These agents are also recognized as the preferred option in the symptomatic treatment of DXM-related psychosis due to their better efficacy and safety profile than typical haloperidol in the short-term course. The focus of the present review concerns the current stage of knowledge about DXM psychotic potency as well as the management of DXM-related psychoses with a special emphasis on atypical antipsychotic drugs (i.e., olanzapine, risperidone, quetiapine, and haloperidol)

Neurokinin-1 receptor-based bivalent drugs in pain management: The journey to nowhere?

Hybrid compounds (also known as chimeras, designed multiple ligands, bivalent compounds) are chemical units where two active components, usually possessing affinity and selectivity for distinct molecular targets, are combined as a single chemical entity. The rationale for using a chimeric approach is well documented as such novel drugs are characterized by their enhanced enzymatic stability and biological activity. This allows their use at lower concentrations, increasing their safety profile, particularly when considering undesirable side effects. In the group of synthetic bivalent compounds, drugs combining pharmacophores having affinities toward opioid and neurokinin-1 receptors have been extensively studied as potential analgesic drugs. Indeed, substance P is known as a major endogenous modulator of nociception both in the peripheral and central nervous systems. Hence, synthetic peptide fragments showing either agonism or antagonism at neurokinin 1 receptor were both assigned with analgesic properties. However, even though preclinical studies designated neurokinin-1 receptor antagonists as promising analgesics, early clinical studies revealed a lack of efficacy in human. Nevertheless, their molecular combination with enkephalin/endomorphin fragments has been considered as a valuable approach to design putatively promising ligands for the treatment of pain. This paper is aimed at summarizing a 20-year journey to the development of potent analgesic hybrid compounds involving an opioid pharmacophore and devoid of unwanted side effects. Additionally, the legitimacy of considering neurokinin-1 receptor ligands in the design of chimeric drugs is discussed

Endomorphin-2- and Neurotensin- Based Chimeric Peptide Attenuates Airway Inflammation in Mouse Model of Nonallergic Asthma

We examined anti-inflammatory potency of hybrid peptide-PK20, composed of neurotensin (NT) and endomorphin-2 (EM-2) pharmacophores in a murine model of non-atopic asthma induced by skin sensitization with 2,4-dinitrofluorobenzene and intratracheal challenge of cognate hapten. Mice received intraperitoneally PK20, equimolar mixture of its structural elements (MIX), dexamethasone (DEX), or NaCl. Twenty-four hours following hapten challenge, the measurements of airway responsiveness to methacholine were taken. Bronchoalveolar lavage (BALF) and lungs were collected for further analyses. Treatment with PK20, similarly to dexamethasone, reduced infiltration of inflammatory cells, concentration of mouse mast cell protease, IL-1&beta;, IL-12p40, IL-17A, CXCL1, RANTES in lungs and IL-1&alpha;, IL-2, IL-13, and TNF-&alpha; in BALF. Simple mixture of NT and EM-2 moieties was less potent. PK20, DEX, and MIX significantly decreased malondialdehyde level and secretory phospholipase 2 activity in lungs. Intensity of NF-&kappa;B immunoreactivity was diminished only after PK20 and DEX treatments. Neither PK20 nor mixture of its pharmacophores were as effective as DEX in alleviating airway hyperresponsiveness. PK20 effectively inhibited hapten-induced inflammation and mediator and signaling pathways in a manner seen with dexamethasone. Improved anti-inflammatory potency of the hybrid over the mixture of its moieties shows its preponderance and might pose a promising tool in modulating inflammation in asthma