An extensive review on antifungal approaches in the treatment of mucormycosis

During the period of COVID-19, the occurrences of mucormycosis in immunocompromised patients have increased significantly. Mucormycosis (black fungus) is a rare and rapidly progressing fungal infection associated with high mortality and morbidity in India as well as globally. The causative agents for this infection are collectively called mucoromycetes which are the members of the order Mucorales. The diagnosis of the infection needs to be performed as soon as the occurrence of clinical symptoms which differs with types of Mucorales infection. Imaging techniques magnetic resonance imaging or computed tomography scan, culture testing, and microscopy are the approaches for the diagnosis. After the diagnosis of the infection is confirmed, rapid action is needed for the treatment in the form of antifungal therapy or surgery depending upon the severity of the infection. Delaying in treatment declines the chances of survival. In antifungal therapy, there are two approaches first-line therapy (monotherapy) and combination therapy. Amphotericin B ( 1 ) and isavuconazole ( 2 ) are the drugs of choice for first-line therapy in the treatment of mucormycosis. Salvage therapy with posaconazole ( 3 ) and deferasirox ( 4 ) is another approach for patients who are not responsible for any other therapy. Adjunctive therapy is also used in the treatment of mucormycosis along with first-line therapy, which involves hyperbaric oxygen and cytokine therapy. There are some drugs like VT-1161 ( 5 ) and APX001A ( 6 ), Colistin, SCH 42427, and PC1244 that are under clinical trials. Despite all these approaches, none can be 100% successful in giving results. Therefore, new medications with favorable or little side effects are required for the treatment of mucormycosis.     

Effects of isolation-rearing on intracranial self-stimulation reward of the lateral hypothalamus: baseline assessment and drug challenges

There is evidence that isolation rearing produces down-regulation of the dopamine D2 receptor. Therefore, isolation rearing should also modify the effects of D2 antagonists on intracranial self-stimulation (ICSS) reward. This study investigated the effect of isolation rearing on ICSS reward, and modulation of that reward by SCH23390, Raclopride and MK-801. Sprague-Dawley rats were reared alone (isolates) or in pairs from day 21 postnatal to day 75 postnatal. At this time, all rats were implanted with monopolar stimulating electrodes in the lateral hypothalamus. The ICSS rate-frequency curve-shift method was used to assess reward and operant motor function at baseline and after administration of SCH-23390 (D1 antagonist: 0.02, 0.06, 0.2 mg/kg), Raclopride (D2 antagonist: 0.01, 0.025, 0.06 mg/kg), and MK-801 (non-competitive NMDA receptor antagonist: 0.1, 0.2 mk/kg). Isolation-reared rats displayed similar measures of both basal reward and motor function when compared to socially reared controls. Isolation-reared rats were subsensitive to the reward decreasing effects of Raclopride. Socially reared rats were observed to have more variant baseline reward measures, and could be divided into distinctly different groups with different basal reward function. Isolation-rearing down-regulates D2 function but does not affect basal reward function, but some unknown factor in the social rearing environment did have a substantial effect on basal reward function.     

[3H]SCH 23390 Binding to Human Putamen D-1 Dopamine Receptors: Stereochemical and Structure-Affinity Relationships Among l-Phenyl-1H-3-Benzazepine Derivatives as a Guide to D-l Receptor Topography

Abstract: A series of l-phenyl-1 H -3-benzazepine analogues were assessed for enantiomeric and structure-affinity relationships at human putamen D-1 dopamine receptors labelled with [³H]SCH 23390. Substitution at the 7-position of both 3-H and 3-methyl benzazepine molecules critically affected affinity for these receptors over a 500-fold range. The general rank order of potency of 7-substituents was Cl = Br ≫ CH₃ > OH ≥ H. 3-Methyl substituents increased the affinity of 7-H and 7-OH compounds two- to fivefold compared to desmethyl counterparts. The displacement of [³H]SCH 23390 binding showed substantial enantioselec-tivity; the R-enantiomer of SKF 83566 was 500-fold more potent that its S-antipode. However, the displacement of [³H]spiperone binding from D-2 sites in the same tissue showed negligible enantioselectivity. Through such structure-affinity relationships, these studies may help to define the topography of the human brain D-1 dopamine receptor and guide the design of more selecive agents for functional studies.     

Molecular probes for the A2A adenosine receptor based on a pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine scaffold

Pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine derivatives such as SCH 442416 display high affinity and selectivity as antagonists for the human A_2A adenosine receptor (AR). We extended ether-linked chain substituents at the p-position of the phenyl group using optimized O-alkylation. The conjugates included an ester, carboxylic acid and amines (for amide condensation), an alkyne (for click chemistry), a fluoropropyl group (for ¹⁸F incorporation), and fluorophore reporter groups (e.g., BODIPY conjugate 14, K_i 15 nM). The potent and A_2AAR-selective N-aminoethylacetamide 7 and N-[2-(2-aminoethyl)-aminoethyl]acetamide 8 congeners were coupled to polyamidoamine (PAMAM) G3.5 dendrimers, and the multivalent conjugates displayed high A_2AAR affinity. Theoretical docking of an AlexaFluor conjugate to the receptor X-ray structure highlighted the key interactions between the heterocyclic core and the binding pocket of the A_2AAR as well as the distal anchoring of the fluorophore. In conclusion, we have synthesized a family of high affinity functionalized congeners as pharmacological probes for studying the A_2AAR.     

Neuroleptics and Dopamine Transporters

The effects of neuroleptic treatments on dopamine transporters and on dopamine receptors was investigated in the forebrain of adult rats treated for 21 days with either haloperidol, clozapine or saline. The dopamine D₁receptors, labeled with [³H]SCH23390, increased in nucleus accumbens, latero-dorsal rostral neostriatum and substantia nigra, after clozapine but not haloperidol. The dopamine D₂receptors, studied with [³H]raclopride, increased in nucleus accumbens and in dorsolateral, ventro-medial and dorso-medial quadrants of the rostral neostriatum after either haloperidol or clozapine treatments, and also in latero-ventral rostral neostriatum but only after haloperidol. Haloperidol also up-regulated D₂receptors in rostral and caudal neostriatum, but clozapine produced a more uneven increase, especially in caudal neostriatum. In contrast, the densities of dopamine uptake sites, or transporters, labeled with [^I25I]RTI-121, remained unchanged after both neuroleptic treatments. The observation that dopamine transporters are resistant to treatments that modify D₁and D₂receptors indicates that these uptake sites can probably be ruled out as the target of neuroleptic drugs, and that dopamine receptor up-regulations can indeed occur independently of the densities of nerve endings at the terminal fields of innervation.     

K-induced alkalinization in all cell types of rabbit gastric glands: A novel K/H exchange mechanism

Digital image processing of the pH-sensitive dye BCECF was used to examine the effects of high [K] media on cytoplasmic pH (pHi) of individual cells within isolated rabbit gastric glands. When cells were acidified to pHi 6.5 from the resting pHi of 7.2-7.3 and then exposed to solution containing 77 mM K plus amiloride (to block Na/H exchange), recovery to pHi 7.0 was observed. This K-induced alkalinization occurred in all cell types of the gland, including cells within antral glands that were devoid of parietal cells (PC). This process was independent of extracellular Na and Cl and was unaffected by: 5 mM Ba or 200 microM bumetanide, or acute treatment with either 500 microM ouabain or 100 microM cimetidine, histamine or carbachol. SCH28080, which inhibits the PC H/K-ATPase when used in the low microM range of concentrations, blocked the K effect on pHi at 100 microM but was ineffective at 1 microM. A similar pHi recovery was also stimulated by Li, Cs (both 72 mM), and Tl (10 mM), in the order Li greater than K greater than Cs greater than Tl (all in the presence of amiloride), and these alkalinizations were also blocked by 100 microM SCH28080. Parallel experiments were performed to test the effect of these ions on 14[C]-aminopyrine accumulation, an index of acid secretion by the H/K-ATPase at the lumenal membrane of the PC. There was no correlation between the rates of cation-induced pHi recovery from an acid load and H secretion as measured by the accumulation of aminopyrine. We conclude that the K- (and Cs- and Li-) dependent pHi recovery is mediated by a novel cation/H exchange mechanism that is distinct from the PC H/K-ATPase.     

Contrasting responses by basal ganglia met-enkephalin systems to low and high doses of methamphetamine in a rat model

The influence of methamphetamine (METH) on basal ganglia met-enkephalin (Menk) was studied by determining levels of this peptide in striatal, pallidal and nigral regions after administering a single low (0.5 mg/kg) or high (10 mg/kg) dose of this stimulant. The Menk levels in the striatal and pallidal areas were reduced and increased after the low- and high-dose METH treatments, respectively, 12 h after drug administration in all striatal and pallidal regions examined. The low-dose effect appeared to be principally influenced by increased activation of the dopamine D2-like receptor, while the high-dose effect seemed to result from dominance of D1-like receptor activation. However, both effects required coactivation of D1- and D2-like receptors. For the most part, both low- and high-dose METH-induced changes in Menk tissue content were fully recovered by 24 h. The Menk levels were not significantly altered in the substantia nigra 3-24 h after either METH treatment. Results reported herein indicated that striatal and pallidal Menk pathways respond differently after acute treatment with low or high doses of METH.     

Effects of Heavy Metal Cations and Other Sulfhydryl Reagents on Brain Dopamine D1 Receptors: Evidence for Involvement of a Thiol Group in the Conformation of the Active Site

To investigate aspects of the biochemical nature of membrane-bound dopamine D1 receptors, rat striatal homogenates were pretreated with heavy metal cations and some other chemical agents, and their effects on D1 receptors were subsequently determined using a standard [3H](R)-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1-N-3- benzazepine([3H]SCH 23390) binding assay. Incubation of striatal membranes with as little as 1 microM Hg2+, 10 microM Cu2+, and 10 microM Cd2+ completely prevented specific [3H]SCH 23390 binding. The effect of Cu2+, 1.5 microM, was noncompetitive in nature, whereas 3-5 microM Cu2+ afforded mixed-type inhibition. The inhibitory effect of Cu2+ was fully reversed by dithiothreitol (0.1-1 mM). Cu2+ (2 microM) did not affect the affinity of cis-flupenthixol or clozapine for remaining [3H]SCH 23390 sites. A second series of cations, Co2+ (30 microM), Ni2+ (30 microM), Mn2+ (1 mM), Ca2+ (25 mM), and Ba2+ (20 mM), inhibited specific [3H]SCH 23390 binding by 50% at the concentrations indicated. The thiol alkylating reagent N-ethylmaleimide (NEM) (0.2 mM) reduced specific binding by 70%. The effect of NEM was completely prevented by coincubation with a D1 receptor saturating concentration of SCH 23390 (20 nM) or dopamine (10 microM). The results indicated that the dopamine D1 receptor is a thiol protein and that a thiol group is essential for the ligand binding.