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Dopamine is a biologically active amine synthesized in the central and peripheral nervous system. This biogenic monoamine acts by activating five types of dopamine receptors (D1–5Rs), which belong to the G protein‐coupled receptor family. Antagonists and partial agonists of D2Rs are used to treat schizophrenia, Parkinson's disease, depression, and anxiety. The typical pharmacophore with high D2R affinity comprises four main areas, namely aromatic moiety, cyclic amine, central linker and aromatic/heteroaromatic lipophilic fragment. From the literature reviewed herein, we can conclude that 4‐(2,3‐dichlorophenyl), 4‐(2‐methoxyphenyl)‐, 4‐(benzo[b]thiophen‐4‐yl)‐1‐substituted piperazine, and 4‐(6‐fluorobenzo[d]isoxazol‐3‐yl)piperidine moieties are critical for high D2R affinity. Four to six atoms chains are optimal for D2R affinity with 4‐butoxyl as the most pronounced one. The bicyclic aromatic/heteroaromatic systems are most frequently occurring as lipophilic appendages to retain high D2R affinity. In this review, we provide a thorough overview of the therapeutic potential of D2R modulators in the treatment of the aforementioned disorders. In addition, this review summarizes current knowledge about these diseases, with a focus on the dopaminergic pathway underlying these pathologies. Major attention is paid to the structure, function, and pharmacology of novel D2R ligands, which have been developed in the last decade (2010–2021), and belong to the 1,4‐disubstituted aromatic cyclic amine group. Due to the abundance of data, allosteric D2R ligands and D2R modulators from patents are not discussed in this review. [ABSTRACT FROM AUTHOR]

Serotonin (5‐hydroxytryptophan [5‐HT]) is a biologically active amine expressed in platelets, in gastrointestinal (GI) cells and, to a lesser extent, in the central nervous system (CNS). This biogenic compound acts through the activation of seven 5‐HT receptors (5‐HT1‐7Rs). The 5‐HT3R is a ligand‐gated ion channel belonging to the Cys‐loop receptor family. There is a wide variety of 5‐HT3R modulators, but only receptor antagonists (known as setrons) have been used clinically for chemotherapy‐induced nausea and vomiting and irritable bowel syndrome treatment. However, since the discovery of the setrons in the mid‐1980s, a large number of studies have been published exploring new potential applications due their potency in the CNS and mild side effects. The results of these studies have revealed new potential applications, including the treatment of neuropsychiatric disorders such as schizophrenia, depression, anxiety, and drug abuse. In this review, we provide information related to therapeutic potential of 5‐HT3R antagonists on GI and neuropsychiatric disorders. The major attention is paid to the structure, function, and pharmacology of novel 5‐HT3R modulators developed over the past 10 years. [ABSTRACT FROM AUTHOR]

Narcolepsy is a rare, chronic neurological disease characterized by excessive daytime sleepiness, cataplexy, vivid hallucinations, and sleep paralysis. Narcolepsy occurs in approximately 1 of 3000 people, affecting mainly adolescents aged 15 to 30 years. Recently, people with narcolepsy were shown to exhibit extensive orexin/hypocretin neuronal loss. The orexin system regulates sleep/wake control via complex interactions with monoaminergic, cholinergic and GABA‐ergic neuronal systems. Currently, no cure for narcolepsy exists, but some symptoms can be controlled with medication (eg, stimulants, antidepressants, etc). Orexin supplementation represents a more sophisticated way to treat narcolepsy because it addresses the underlying cause of the disease and not just the symptoms. Research on orexin supplementation in the treatment of sleep disorders has strongly increased over the past two decades. This review focuses on a brief description of narcolepsy, the mechanisms by which the orexin system regulates sleep/wake cycles, and finally, possible therapeutic options based on orexin supplementation in animal models and patients with narcolepsy. [ABSTRACT FROM AUTHOR]

Tacrine was the first drug to be approved for Alzheimer's disease (AD) treatment, acting as a cholinesterase inhibitor. The neuropathological hallmarks of AD are amyloid-rich senile plaques, neurofibrillary tangles, and neuronal degeneration. Squaramides (SQ) are derivatives of squaric acid that are widely used in a variety fields of experties. Examples of small molecules with incorporated squaramide scaffold are Perzinfotel or Navarixin. Considering the relatively simple synthesis approach and other interesting properties (rigidity, aromatic character, H-bond formation) of squaramide motif, we developed 21 novel dimers amalgamating squaric acid with either tacrine, 6-chlorotacrine or 7-methoxytacrine representing various acetylcholinesterase inhibitors (AChEIs). All new derivatives were evaluated for their anti-cholinesterase activities, hepatotoxicity and screened to predict their ability to cross the blood-brain barrier. In ongoing study, we also demonstrate that a common butyrylcholinesterase variant confers resistance to tacrine, which can be overcome by using derivatives from tacrinesquaramaide family. These findings underscore the importance of genetic drug target variability for personalized medicine. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive brain disorder with characteristic symptoms and several pathological hallmarks. The concept of "one drug, one target" has not generated any new drugs since 2004. The new era of drug development in the field of AD builds upon rationally designed multi-target directed ligands that can better address the complexity of AD (1). Herewith, we designed ten novel derivatives of 2-propargylamino-naphthoquinone. The biological evaluation of these compounds includes inhibition of monoamine oxidase A/B, inhibition of amyloidbeta aggregation, radical-scavenging, and metal-chelating properties. Some of the compounds possess low cytotoxicity profile with an anti-inflammatory ability in the lipopolysaccharide-stimulated cellular model. All these features warrant their further testing in the field of AD (2). [ABSTRACT FROM AUTHOR]

Since 2002, no clinical candidate against Alzheimer's disease has reached the market; hence, an effective therapy is urgently needed. We followed the so-called "multitarget directed ligand" approach and designed 36 novel tacrine phenothiazine heterodimers which were in vitro evaluated for their anticholinesterase properties. The assessment of the structure-activity relationships of such derivatives highlighted compound 1dC as a potent and selective acetylcholinesterase inhibitor with IC50 = 8 nM and 1aA as a potent butyrylcholinesterase inhibitor with IC50 = 15 nM. Selected hybrids, namely, 1aC, 1bC, 1cC, 1dC, and 2dC, showed a significant inhibitory activity toward τ(306-336) peptide aggregation with percent inhibition ranging from 50.5 to 62.1%. Likewise, 1dC and 2dC exerted a remarkable ability to inhibit self-induced Aβ1-42 aggregation. Notwithstanding, in vitro studies displayed cytotoxicity toward HepG2 cells and cerebellar granule neurons; no pathophysiological abnormality was observed when 1dC was administered to mice at 14 mg/kg (i.p.). 1dC was also able to permeate to the CNS as shown by in vitro and in vivo models. The maximum brain concentration was close to the IC50 value for acetylcholinesterase inhibition with a relatively slow elimination half-time. 1dC showed an acceptable safety and good pharmacokinetic properties and a multifunctional biological profile. [ABSTRACT FROM AUTHOR]

In this pilot study, a series of new 3,4-dihydroquinolin-2(1H)-one derivatives as potential dopamine receptor D2 (D2R) modulators were synthesized and evaluated in vitro. The preliminary structure–activity relationship disclosed that compound 5e exhibited the highest D2R affinity among the newly synthesized compounds. In addition, 5e showed a very low cytotoxic profile and a high probability to cross the blood–brain barrier, which is important considering the observed affinity. However, molecular modelling simulation revealed completely different binding mode of 5e compared to USC-D301, which might be the culprit of the reduced affinity of 5e toward D2R in comparison with USC-D301. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by a severe, progressive loss of memory. Currently, AD therapy is limited on the administration of cholinesterase inhibitors (ChEIs) and the N-methyl-D-aspartate (NMDA) antagonist, memantine. Tacrine as the first registered acetylcholinesterase (AChE, E.C. 3.1.1.7) inhibitor was withdraw due to its adverse effects. 7-Methoxytacrine (7-MEOTA) was prepared as a pharmacologically equal active compound with lower toxicity compared to THA. Donepezil as a highly selective inhibitor for AChE was connected with 7-MEOTA scaffold due to the ability to interact within calatytic anionic site (CAS) as well as peripheral anionic site (PAS) regions of AChE [1]. Recent research has been focused on studying the association between the intracellular amyloid beta (Aß) cascade and the dysfunction of subcellular organelles, especially mitochondria. Mitochondrial enzyme amyloid beta binding alcohol dehydrogenase (ABAD) might contribute to the neuronal dysfunction associated with AD by interacting with intracellular Aß [2]. These derivatives embodying 7-MEOTA and donepezil moieties [3] could be effective in the treatment of AD with the respect of their ability to interact with the multiple targets. Within our contribution, synthesis, in vitro biological evaluation including cholinesterase inhibitory activity and effects on mitochondrial function of 7-MEOTA-donepezil series will be reported. [ABSTRACT FROM AUTHOR]