G-protein-coupled receptors: the new dopamine receptor subtypes.

The family of genes encoding G-protein-coupled dopamine receptors continues to grow with the recent cloning of a fifth member. The availability of these clones has revolutionized the dopamine receptor field. Expression of individual dopamine receptors is permitting the detailed analysis of their pharmacology and coupling to second messenger systems, while probes based on the receptors' nucleotide sequences are being used to gain new insights into their tissue distribution and genetics.     

Serendipitous discovery of a new class of agonists for the melanocortin 1 and 4 receptors and a new class of cyclophanes

A new class of melanocortin 4 receptor (MC4r) agonists was discovered from an unexpected sidereaction in which formaldehyde caused cyclization. These cyclophanes were found to be sub micromolar agonists of the MC1 and MC4 and were less potent on the MC3 and MC5 receptor. They were shown to compete with the peptidic antagonist SHU9119 for binding to the MC4 receptor. In an acute feeding study in Sprague Dawley rats, food intake was reduced more than 50% versus vehicle after 3 h at a dose of 1 mg/kg.     

Esculentosides: Insights into the potential health benefits,mechanisms of action and molecular targets

BackgroundEsculentosides and related phytolaccosides form a group of oleanene-type saponins isolated from plants of the Phytolaccaceae family, essentially Phytolacca esculenta, P. americana and P. acinosa. This chemical family offers a diversity of glycosylated compounds, including molecules with a mono-, di- or tri-saccharide unit at position C-3, and with or without a glucose residue at position C-28. The esculentosides, which derive essentially from the sapogenin jaligonic acid or its 30-methyl ester phytolaccagenin, exhibit anti-inflammatory, antifungal and anticancer activities.PurposeThe objective of the review was to identify the 26 esculentosides (ES) and phytolaccosides known to date, including 16 monodesmosidic and 10 bidesmosidic saponins, and to review their pharmacological properties and molecular targets.MethodologyThe retrieval of potentially relevant studies was done by systematically searching of scientific databases like Google Scholar and PubMed in January-May 2020. The main keywords used as search terms were related to esculentosides, phytolaccosides and Phytolaccaceae. The systematic search retrieved about 110 papers that were potentially relevant and after an abstract-based selection, 68 studies were analyzed in details and discussed.ResultsThe structural relationship between the compounds and their sapogenin precursors has been studied. In addition, the pharmacological properties of the main ES, such as ES-A, -B and -H, have been analyzed to highlight their mode of action and potential targets. ES-A is a potent inhibitor of the release of cytokines and this anti-inflammatory activity contributes to the anticancer effects observed in vitro and in vivo. Potential molecular targets of ES-A/B include the enzymes cyclooxygenase 2 (COX-2) and casein kinase 2 (CK2). In addition, the targeting of the protein high-mobility group box 1 (HGMB1) by ES-A/B is proposed, based on molecular modeling and the structural analogy with the related saponin glycyrrhizin, a potent HGMB1 alarmin inhibitor.ConclusionMore work is needed to properly characterize the molecular targets but otherwise compounds like ES-A and ES-H emerge as potent anti-inflammatory and anticancer agents and ES-B as an antifungal agent. A preclinical development of these three compounds should be considered.     

Triazole incorporated pyridazinones as a new class of antihypertensive agents: design, synthesis and in vivo screening

A number of 6-(substituted phenyl)-2-(4-substituted phenyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-4,5-dihydropyridazin-3(2H)-one derivatives were designed and synthesized by a sequence of reactions starting from respective aryl hydrocarbons. The final compounds (4a-4u) were evaluated for antihypertensive activities by non-invasive method using Tail Cuff method. The compounds 4e, 4i and 4k showed appreciable antihypertensive activity comparable with that of standard hydralazine and propranolol.     

Narcotic dependence, narcotic action and dopamine receptors.

Acute systematic administration of narcotic analgesics increases the firing rate of nerve cells in the zona compacta of the substantia nigra, causes an increase in the rate of dopamine turnover in striatal and mesolimbic areas of the brain, stimulates prolactin release, inhibits brain self-stimulation and discriminated shock-avoidance, blocks cardiovascular effects of systemically injected dopamine, blocks aggression as well as compulsive jumping in mice treated with DOPA and amphetamine, antagonizes stereotypy induced by apomorphine or amphetamine, and blocks apomorphine-induced vomiting in dogs. Chronic administration of narcotic analgesics results in withdrawal signs upon the cessation of the drug administration. These signs include, tolerance to the increase in striatal dopamine turnover caused by narcotic analgesics or haloperidol, aggressive behaviors which are further stimulated by directly or indirectly acting dopamine-receptor agonists and are blocked by dopamine-receptor blockers, facilitation of recovery from the “lateral hypothalamic syndrome”, an increase in basal levels of striatal adenylate cyclase which shows greater sensitivity to dopamine, and, an enhanced sensitivity to apomorphine-induced reduction of dopamine turnover. It is therefore, concluded that acute administration of narcotic drugs results in an inhibition of dopamine-receptor activity while chronic administration of these drugs results in an increased response of these dopamine receptors to dopamine agonists. Recent experiments on the interaction of other drugs with narcotic analgesics suggest that, unlike the direct action of neuroleptics on the dopamine receptors, the narcotic action on dopamine receptors is indirect.     

Characterization of a new class of selective nonsteroidal progesterone receptor agonists

The identification of a new series of selective nonsteroidal progesterone receptor (PR) agonists is reported. Using a high-throughput screening assay based on the measurement of transactivation of a mouse mammary tumor virus promoter-driven luciferase reporter (MMTV-Luc) in human breast cancer T47D cells, a benzimidazole-2-thione analog was identified. Compound 1 showed an apparent EC50 of 53 nM and efficacy of 93% with respect to progesterone. It binds to PR with high affinity (Ki nM), but had no or very low affinity for other steroid hormone receptors. Structure-activity relationship studies of a series of benzimidazole-2-thione analogs revealed critical positions for high PR binding affinity and transactivation potency as well as receptor selectivity, as exemplified by 25. Compound 25 binds to human PR with high affinity (Ki nM) and had at least > 1000-fold selectivity for PR versus other steroid receptors. Molecular modeling studies suggested that these agonists overlap favorably with progesterone in the ligand-binding domain of PR. In T47D cells, compound 25 acted as a full agonist in the MMTV-Luc reporter assay, as well as in the induction of endogenous alkaline phosphatase activity with apparent EC50 values of 4 and 9 nM, respectively. In the immature rat model, compound 25 provided a significant suppression of estrogen-induced endometrium hypertrophy as measured by luminal epithelial height. In contrast, compound 25 was inactive in the luteinizing hormone release assay in young ovariectomized rats. These benzimidazole-2-thione analogs constitute a new series of nonsteroidal PR agonists with an excellent steroid receptor selectivity profile. The differential activities observed in the in vivo progestogenic assays in rat models suggest that these analogs can act as selective PR modulators.     

Development of a new class of potential antiatherosclerosis agents: NO-donor antioxidants

A new class of NO-donor phenol derivatives is described. The products were obtained by joining appropriate phenols with either nitrooxy or 3-phenylsulfonylfuroxan-4-yloxy moieties. All the compounds proved to inhibit the ferrous salt/ascorbate induced lipidic peroxidation of membrane lipids of rat hepatocytes. They were also capable of dilating rat aorta strips precontracted with phenylephrine.     

2-Arylimino-5,6-dihydro-4H-1,3-thiazines as a new class of cannabinoid receptor agonists. Part 2: orally bioavailable compounds

Structure-activity relationships and efforts to optimize the pharmacokinetic profile of a class of 2-arylimino-5,6-dihydro-4H-1,3-thiazines as cannabinoid receptor agonists are described. Among the compounds examined, compound 14 showed potent affinity and high selectivity for CB2, and compound 23 showed potent affinities against CB1 and CB2. These compounds displayed oral bioavailability.     

Novel dihydropyrimidines as a potential new class of antitubercular agents

A small library of 30 dihydropyrimidines was synthesized and evaluated for their in vitro antitubercular activity against Mycobacterium tuberculosis H₃₇Rv. Two compounds, ethyl 4-[3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl]-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5 carboxylate 4a and ethyl 4-[3-(4-nitrophenyl)-1-phenyl-1H-pyrazol-4-yl]-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate 4d were found to be the most active compounds in vitro with MIC of 0.02 μg/mL against MTB and were more potent than isoniazid.     

Synthesis and preliminary biological characterization of a new potential I-Radioligand for dopamine and serotonin receptors

The synthesis and a preliminary biological characterization of a new class of N-benzyl-aminoalcohols which have serotonin (5-HT₂) and dopamine (D₂) receptor affinity is described. In vitro competition binding studies were conducted with the new molecules and ³H-spiperone on crude membrane preparation from rat striatum and frontal cortex. One of these compounds, 3-benzylamino-1-(4-fluoro-2-iodophenyl)-propan-1-ol (6f), whose IC₅₀ values are in the micromolar range for both the D₂ and 5-HT₂ receptors, was prepared in iodine-125 labelled form (6i) by nucleophilic substitution of the bromine atom of 3-benzylamino-1-(2-bromo-4-fluorophenyl)-propan-1-ol (6d). In the in vivo studies, conducted on rats, the radiolabelled molecule 6i shows a good capacity to cross the blood–brain barrier (BBB) with a mean value of first pass cerebral extraction (E) of ca. 50% when the regional cerebral blood flow, measured with microsphere technique, is in the experimental animal's physiologic range (0.8–1 mL/min/g). A preliminary in vitro autoradiographic distribution on coronal rat brain slices of the radioiodinated molecule showed that it was preferentially localized in the striatum and in the cerebral regions rich in dopamine- and serotonin receptors, even if a high non-specific binding was observed.     

Adenosine diphosphate receptors on blood platelets: potential new targets for antiplatelet therapy

Platelets play a key role not only in physiological haemostasis, but also under pathological conditions such as thrombosis. Platelet activation may be initiated by a variety of agonists including thrombin, collagen, thromboxane or adenosine diphosphate (ADP). Although ADP is regarded as a weak agonist of blood platelets, it remains an important mediator of platelet activation evoked by other agonists, which induce massive ADP release from dense granules, where it occurs in molar concentrations. Thus, ADP action underlies a positive feedback that facilitates further platelet aggregation and leads to platelet plug formation. Additionally, ADP acts synergistically to other, even weak, agonists such as serotonin, adrenaline or chemokines. Blood platelets express two types of P2Y ADP receptors: P2Y(1) and P2Y(12). ADP-dependent platelet aggregation is initiated by the P2Y1 receptor, whereas P2Y(12) receptor augments the activating signal and promotes platelet release reaction. Stimulation of P2Y(12) is also essential for ADP-mediated complete activation of GPIIb-IIIa and GPIa-IIa, and further stabilization of platelet aggregates. The crucial role in blood platelet biology makes P2(Y12) an ideal candidate for pharmacological approaches for anti-platelet therapy.     

Stroke: molecular mechanisms and potential targets for treatment

Significant advances have been made over the past few years concerning the cellular and molecular events underlying ischemic cell death. The brain succumbs to ischemic injury as a result of loss of metabolic stores, excessive intracellular calcium accumulation, oxidative stress, and potentiation of the inflammatory response. Neurons can also die via necrotic or apoptotic mechanisms, depending on the nature and severity of the insult. While it has been widely held that ischemia is notable for cessation of protein synthesis, brain regions with marginal reduction in blood supply are especially capable of expressing a variety of genes, the functions of many of which are only beginning to be understood. Gene expression is also upregulated upon reperfusion and reoxygenation. As a result, a number of signaling pathways have been identified and are now known to contribute to ischemic progression or, in some cases, attempts at self preservation. This review will focus on the roles of stress genes, apoptosis-related genes, and inflammation. Knowledge of such molecular events has fueled interest in developing specific molecular targets with the hope of someday affecting outcome in clinical stroke.     

2-Arylimino-5,6-dihydro-4H-1,3-thiazines as a new class of cannabinoid receptor agonists. Part 1: discovery of CB2 receptor selective compounds

2-Arylimino-5,6-dihydro-4H-1,3-thiazines have been identified as a novel class of cannabinoid agonists. A lead structure with moderate activity was discovered through a high throughput screening assay. Structure-activity relationships led to the discovery of potent agonists of CB(2) receptor. The most potent compound 13 displays K(i) values of >5000 and 9 nM to CB(1) and CB(2) receptors, respectively.     

1- and 2-substituted naphthalenes: a new class of potential hypotensive agents

A series of 2-substituted aminomethyloxy naphthalenes 1 and 4-(1-naphthoxy-2-substituted aminomethyl)-butanoic acids 2 were synthesized by Mannich reaction of 4-(2-naphthoxy)-butanoic acid 3 and 4-(1-naphthoxy)-butanoic acid 4 with appropriate secondary amines and para-formaldehyde. The newly synthesized compounds were tested for their hypotensive activity at 5 mg/kg i.v. dose in cats. The results indicated that the analogue 2-(N4-phenyl-N1-piperazino)-methyloxy naphthalene 1d (> N = N4-phenyl-N1-piperazino) was the most active analogue when its hypotensive activity was compared to the reference compound propranolol.     

2-Arylimino-5,6-dihydro-4H-1,3-thiazines as a new class of cannabinoid receptor agonists. Part 3: Synthesis and activity of isosteric analogs

Structure-activity relationships and efforts to optimize the pharmacokinetic profile of isosteric analogs of 2-arylimino-5,6-dihydro-4H-1,3-thiazines as cannabinoid receptor agonists are described. Among those examined, compound 25 showed potent affinity for cannabinoid receptor 1 (CB1) and receptor 2 (CB2). This compound displayed oral bioavailability and analgesic activity.     

Sites and mechanisms of action of melatonin in mammals: the MT1 and MT2 receptors

The rhythmic secretion of melatonin by the pineal gland plays a key role in the synchronisation of circadian and seasonal functions with cyclic environmental variations. The biological effects of this neurohormone are relayed mainly by G-protein-coupled seven-transmembrane receptors. These receptors, known as MT1 and MT2, are present in a large number of central and peripheral structures in mammals, with considerable inter-species variations. However, only the suprachiasmatic nuclei of the hypothalamus, the site of the master circadian biological clock, and the pars tuberalis of the adenohypophysis contain melatonin receptors in the majority of species. Inhibition of the production of AMPc by a Gi/Go protein is one of the principal signalling pathways of the MT1 and MT2 receptors, although many other signal transduction pathways are also brought into play according to the cell type studied (PKC, Ca2+, K+ channels or GMPc in the case of MT2, etc.). Numerous factors or physiological stimuli are capable of influencing the number and functional status of the MT1 and MT2 receptors, such as melatonin, the photoperiod, the circadian clock or the phenomena of receptor dimerisation. Melatonin has numerous physiological effects for which the mechanisms of action and the specific role of the MT1 and MT2 receptors have not yet been clearly elucidated. However, selective pharmacological tools for each of the two receptor subtypes are currently being identified, notably in the Servier Group, for the purpose of furthering our knowledge of the functionality and physiological role of the MT1 and MT2 receptors in the central and peripheral structures.