The synthetic CB1 cannabinoid receptor selective agonists: Putative medical uses and their legalization.

More than 500 molecules have been identified as components of Cannabis sativa (C. sativa), of which the most studied is Δ9-tetrahydrocannabinol (Δ9-THC). Several studies have suggested that Δ9-THC exerts diverse biological effects, ranging from fragmentation of DNA to behavioral disruptions. Currently, it is accepted that most of the pharmacological properties of Δ9-THC engage the activation of the cannabinoid receptors, named CB1 and CB2. Interestingly, multiple pieces of evidence have suggested that the cannabinoid receptors play an active role in the modulation of several diseases leading to the design of synthetic cannabinoid-like compounds. Advances in the development of synthetic CB1 cannabinoid receptor selective agonists as therapeutical approaches are, however, limited. This review focuses on available evidence searched in PubMed regarding the synthetic CB1 cannabinoid receptor selective agonists such as AM-1235, arachidonyl-2' chloroethylamide (ACEA), CP 50,556-1 (Levonantradol), CP-55,940, HU-210, JWH-007, JWH-018, JWH-200 (WIN 55,225), methanandamide, nabilone, O-1812, UR-144, WIN 55,212-2, nabiximols, and dronabinol. Indeed, it would be ambitious to describe all available evidence related to the synthetic CB1 cannabinoid receptor selective agonists. However, and despite the positive evidence on the positive results of using these compounds in experimental models of health disturbances and preclinical trials, we discuss evidence in regards some concerns due to side effects.

Synthesis of Quercetin-Metal Complexes, In Vitro and In Silico Anticholinesterase and Antioxidant Evaluation, and In Vivo Toxicological and Anxiolitic Activities.

The level of acetylcholine, a neurotransmitter essential for processing memory and learning, is lower in the brains of patients with Alzheimer's disease due to the higher concentration of the enzyme acetylcholinesterase. The main compounds used for Alzheimer's treatment are acetylcholinesterase inhibitors. Quercetin coordination complexes with the metal ions Cu+2, Zn+2, Ni+2, Co+2, and Fe+2 were synthesized to investigate their potential use against Alzheimer's disease, by evaluating the inhibition of acetylcholinesterase in vitro and in silico, as well as the antioxidant activity, toxicity, and anxiolytic action in the zebrafish (Danio rerio) model. The organic complexes were characterized by UV-Vis and FT-IR. The spectral information suggested that coordination of metals occurs with the carbonyl group and OH linked to the C-3 carbon of quercetin. The quercetin-Fe (QFe) complex presented the best antioxidant and antiacetylcholinesterase actions, and these results were confirmed by molecular docking. In the toxicity and locomotor evaluation, the quercetin molecules and the synthesized complexes, mainly QCu and QZn derivatives, showed the highest degree of inhibition of the fish's locomotor activity, suggesting a possible anxiolytic action. Then, quercetin complexes with metals, mainly with Fe+2, represent valuable compounds and deserve more investigation as promising agents against Alzheimer's disease.

Synthesis, Computational and Pharmacological Evaluation of N-(2-benzoyl- 4-chlorophenyl)-2-(4-(Substituted Phenyl) Piperazin-1-yl) Acetamides as CNS Agents.

BACKGROUND: A series of new N-(2-benzoyl-4-chlorophenyl)-2-(4-(substituted phenyl) piperazin-1-yl) acetamides (3a-j) have been synthesized by the chloroacetylation of 2-amino-5- chlorbenzophenone which was further reacted with substituted phenylpiperazine. MATERIAL: The chemical structures of the compounds were confirmed on the basis of their TLC, IR, 1HNMR, 13CNMR and by elemental analysis. The physicochemical similarity of the target compounds with respect to standard drug diazepam was assessed by calculating from a set of physicochemical properties using software programs. CONCLUSION: Molecular docking studies revealed that the target compounds correctly dock into the binding pocket of the GABAA receptor, while their bioavailability/drug-likeness was predicted to be acceptable but requires future optimization. The anxiolytic and skeletal muscle relaxant activity of the target compounds (3a-j) were evaluated in albino mice. Among them, compound 3h showed potent anxiolytic and skeletal muscle relaxant activity.

The first dipeptide ligand of translocator protein: Design and anxiolytic activity.

On the basis of the structure of Alpidem, a pyrazolopyrimidine ligand of the translocator protein (TSPO), a dipeptide TSPO ligand, N-carbobenzoxy-L-tryptophanyl-L-isoleucine amide (GD-23), was designed and synthesized using our own original peptide design strategy. This compound exhibited anxiolytic activity in BALB/cAnN mice in the "open-field" test and in outbred CD1 mice in the "elevated plus maze" test. The stereoselectivity of the anxiolytic effect of GD-23 is demonstrated. The results of this study suggest that GD-23 is a ligand of the translocator protein, and its structure can become the basis for creating anxiolytics with a fundamentally new mechanism of action.

Identification of alpha-substituted acylamines as novel, potent, and orally active mGluR5 negative allosteric modulators.

This Letter describes the identification of a series of novel non-acetylenic mGluR5 negative allosteric modulators based on the alpha-substituted acylamine structure. An initial structure-activity relationship study suggested that (R)-19b and (R)-19j might have good in vitro activity. When administered orally, these compounds were found to have an anxiolytic-like effect in a mouse model of stress-induced hyperthermia.

The biological activity of derivatives of 2-[(o-; and p-substituted)aminophenyl]-3H-5-[(o-; and p-substituted)phenyl]-7-chloro-1,4-benzodiazepines and 1-alkyl-3H-5-[(o-; and p- substituted) phenyl]-7-chloro-1,4-benzodiazepin-2-one.

Eight of a series of twelve new 2-[(o-; and p-substituted)aminophenyl]-3H-5-[(o-; and p-substituted)phenyl]-7-chloro-1,4-benzodiazepinines (VI, 1-12; Fig. 1) and two of eleven new 1-alkyl-3H-5-[(o-; and p-substituted)phenyl]-7-chloro-1,4-benzodiazepin-2-one (IV, 1-12; Fig. 2) were tested for their pharmacological and/or biological activity as anxiolytics.

Rational design, synthesis, and structure-activity relationship of benzoxazolones: new potent mglu5 receptor antagonists based on the fenobam structure.

A novel class of potent and stable mGlu5 receptor antagonists was developed by combining information from a high-throughput screening campaign with the structure of the known anxiolytic fenobam. Representative compounds from this class show favorable pharmacokinetic properties and are active in an in vivo model of anxiety.

Piperazinyl oxime ethers as NK-1 receptor antagonists.

The synthesis and structure-activity relations for a new class of centrally active NK-1 receptor antagonists are described. The new compounds are based on piperazine 2 and contain an oxime ether functionality. Several new compounds have high affinity for the NK-1 receptor and show good antagonistic activity in the gerbil foot-tapping assay.

Cyclic urea derivatives as potent NK1 selective antagonists. Part II: Effects of fluoro and benzylic methyl substitutions.

A series of novel five-membered urea derivatives as potent NK1 receptor antagonists is described. The effects of substitution of a 4-fluoro group at the phenyl ring and the introduction of an alpha-methyl group at the benzylic position to improve potency and duration of in vivo activity are discussed. Several compounds with high affinity and sustained in vivo activity were identified.

Synthesis and 5-HT(1A), 5-HT(2A) receptor activity of new beta-tetralonohydantoins.

A series of new 3-[4-(4-arylpiperazinyl)-butyl]-beta-tetralonohydantoins (8a-13a) were synthesized. The compounds exhibited high affinity for 5-HT(1A) receptors (K(i)=6 to 55 nM) combined with moderate-to-high 5-HT(2A) receptor affinities (K(i)=45 to 213 nM). The results of in vivo studies indicated that of the compounds tested, 3-[4-(4-phenylpiperazinyl)-butyl-beta-tetralonohydantoin (8a) showed features of full (pre- and postsynaptic) 5-HT(1A) receptor agonists, whereas compounds 9a-13a behaved like antagonists of postsynaptic 5-HT(1A) receptors; additionally, compound 13a produced an effect characteristic of presynaptic 5-HT(1A) receptor agonists. Moreover, compounds 8a and 10a-13a exhibited properties of 5-HT(2A) receptor antagonists. Due to the most interesting 5-HT(1A)/5-HT(2A) functional profile compounds 8a and 13a were further tested for their potential psychotropic activity. In fact, compound 8a (but not 13a) showed diazepam-like anxiolytic activity and behaved like a weak antidepressant.

Synthesis of (1S,3aS)-8-(2,3,3a,4,5, 6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triaza-spiro[4. 5]decan-4-one, a potent and selective orphanin FQ (OFQ) receptor agonist with anxiolytic-like properties.

The development of 8-(2,3,3a,4,5, 6-hexahydro-1H-phenalen1-yl)-1-phenyl-1,3,8-triaza-spiro[4. 5]decan-4-ones 3 starting from (RS)-8-acenaphten-1-yl-1-phenyl-1,3, 8-triazaspiro[4.5]decan-4-one 1 is reported. The synthesis and the binding affinities at human OFQ and opioid (micro, kappa, delta) receptors of the stereoisomers 3a-f are described. In vitro the most selective compound, (1S,3aS)-8-(2,3,3a,4,5, 6-hexahydro-1H-phenalen1-yl)-1-phenyl-1,3,8-triaza-spiro[4. 5]decan-4-one 3c, was found to act as a full agonist at the OFQ receptor in the GTPgamma(35)S binding test. It turned out to be selective versus a variety of other neurotransmitter systems. When tested in vivo following intraperitoneal injection, compound 3c was found to decrease neophobia in a novel environment and to exhibit dose-dependent anxiolytic-like effects in the elevated plus-maze procedure, thus confirming the effects observed following intracerebroventricular infusion of the OFQ peptide in rat.

Piperazine imidazo[1,5-a]quinoxaline ureas as high-affinity GABAA ligands of dual functionality.

A series of imidazo[1,5-a]quinoxaline piperazine ureas appended with a tert-butyl ester side chain at the 3-position was developed. Analogues within this series have high affinity for the gamma-aminobutyric acid A (GABAA)/benzodiazepine receptor complex with efficacies ranging from inverse agonists to full agonists. Many analogues were found to be partial agonists as indicated by [35S]TBPS and Cl- current ratios. Uniquely, a number of these analogues were found to have a bell-shaped dose-response profile in the alpha1 beta2 gamma2 subtype as determined by whole cell patch-clamp technique, where in vitro efficacy was found to decrease with increasing drug concentration. Many of the compounds from this series were effective in antagonizing metrazole-induced seizures, consistent with anticonvulsant and possibly anxiolytic activity. Additionally, several analogues were also effective in lowering cGMP levels (to control values) after applied stress, also consistent with anxiolytic-like properties. The most effective compounds in these screens were also active in animal models of anxiety such as the Vogel and Geller assays. The use of the piperazine substituent allowed for excellent drug levels and a long duration of action in the central nervous system for many of the quinoxalines, as determined by ex vivo assay. Pharmacokinetic analysis of several compounds indicated excellent oral bioavailability and a reasonable half-life in rats. From this series emerged two partial agonists (55, 91) which had good activity in anxiolytic models, acceptable pharmacokinetics, and minimal benzodiazepine-type side effects.

Synthesis and pharmacological properties of new derivatives of 4-methyl-5-oxalo-1H-2,3,4,5-tetrahydro-1,5-benzodiazepin-2-one and beta-oxo-5-(4-methyl-1H-2,3,4,5-tetrahydro-1,5-benzodiazepin-2 -one)propionic acid.

5-Ethoxalyl 4-methyl-1H-2,3,4,5-tetrahydro 1,5-benzodiazepin-2 -one [I] and 5-ethoxymalonyl-4-methyl-1H-2,3,4,5-tetrahydro-1,5-benzodiazepi n-2-one [IV] were subjected to transesterification using alcohols (propanol, butanol, pentanol) giving derivatives II-IV, VII, VIII. The derivatives I and VI were caused to undergo ammonolysis giving 4-methyl-5-oxamoyl-1H-2,3,4,5 tetrahydro 1,5-benzodiazepin-2-one [V] and 5-malonamoyl-4-methyl-1H-2,3,4,5-tetrahydro-1,5-benzodiazepin++ +-2-one [IX]. The compounds I-IX were tested towards their psychotropic activity. The preparates I, III and V had an anxiolytic action in the four-plate test. The anxiolytic properties of the compound V were confirmed in the test of the black-white box. The antagonism of all investigated compounds for toward reserpine, first of all of the preparations III, IV, V and IX, indicates an antidepressive activity dependent on a stimulation of the adrenergic system.

Cholecystokinin dipeptoid antagonists: design, synthesis, and anxiolytic profile of some novel CCK-A and CCK-B selective and "mixed" CCK-A/CCK-B antagonists.

The design, synthesis, and structure-activity relationships (SAR) for the development of selective dipeptoid ligands for both of the cholecystokinin (CCK) receptor subtypes CCK-A and CCK-B are described. The SAR developed is used to design a ligand with equal nanomolar binding affinity for both the CCK-A and CCK-B receptors. Example compounds such as [1R-[1 alpha[R*(R*)],2 beta]]-4-[[2-[[3-(1H-indol-3-yl)- 2-methyl-2-[[[(2-methylcyclohexyl)oxy]carbonyl]amino]-1- oxopropyl]-amino]-1-phenylethyl]amino]-4-oxo-butanoic acid (24c), (1R-trans)-N-[alpha-methyl-N-[[(2-methylcyclohexyl)oxy] carbonyl]-D-tryptophyl]-L-3-(phenylmethyl)-beta-alanine (28i), and N-[alpha-methyl-N-[(tricyclo[3.3.1.1]dec-2-yloxy) carbonyl]-D-tryptophanyl]-L-3-(phenylmethyl)-beta-alanine (30m) are CCK-B selective compounds having CCK-B binding affinities of IC50 = 3.9, 0.34, and 0.15 nM with a CCK-A/CCK-B ratio of 464, 53, and 170, respectively. Other compounds such as (1R-trans)-N-[alpha-methyl-N-[[(2-methylcyclohexyl)oxy]carbonyl]- L-tryptophyl]-D-3-(phenylmethyl)-beta-alanine (281) and N-(alpha-methyl-N-[(tricyclo[3.3.1.1]dec-2-yloxy)carbonyl]-L - tryptophyl]-D-3-(phenylmethyl)-beta-alanine (30p) are CCK-A-selective compounds having CCK-A binding affinities of IC50 = 7.9 and 2.82 nM with a CCK-A/CCK-B ratio of 0.007 and 0.01, respectively. Further to these, (1S-trans)-N-[alpha-methyl-N-[[(2-methylcyclohexyl)oxy] carbonyl]-D-tryptophyl]-L-3-(phenylmethyl)-beta-alanine (28h) is a mixed CCK-A/CCK-B ligand with a CCK-A binding affinity of IC50 = 3.9 nM and a CCK-B binding affinity of IC50 = 4.2, producing a CCK-A/CCK-B ratio of unity. The CCK-B selective compounds are shown to be antagonists in electrophysiological tests on the rat ventromedial nucleus of the hypothalamus with an equilibrium constant (Ke) value of 2.8 nM for 30m and are also shown to be anxiolytic in the mouse ligh/dark box test with a minimum effective dose of 0.01 mg/kg, sc, for 30m. The CCK-A selective compounds are also shown to be competitive antagonists by the inhibition of CCK-8S-evoked amylase secretion from pancreatic acinar cells with a Ke value of 16 nM for 30p. In electrophysiological tests on the rat dorsal raphé (an area rich in CCK-A receptors) 30p had a Ke value of 12.8 nM. The mixed CCK-A/CCK-B compound 28h showed antagonistic properties in both CCK-A and CCK-B models; thus it inhibited CCK-8S-evoked amylase secretion from pancreatic acinar cells and is anxiolytic in the light/dark box paradigm.(ABSTRACT TRUNCATED AT 400 WORDS)

2-benzazepines. 5. Synthesis of pyrimido[5,4-d][2]benzazepines and their evaluation as anxiolytic agents.

A series of 5H-pyrimido[5,4-d][2]benzazepines has been synthesized, starting from the corresponding 2-benzazepin-5-ones, and evaluated as potential anxiolytic agents. Selected compounds from this series show a pharmacological profile of action different than that of diazepam. They are more potent than diazepam in the anti-pentylenetetrazole test and in the [3H]diazepam binding assay, yet show less activity in the inclined screen test. A pharmacological data profile is given for 9-chloro-7-(2-chlorophenyl)-5H-pyrimido[5,4-d] [2]benzazepine (7c). The structure-activity relationships of these potential anxiolytic agents are discussed.