thioperamide and imidazole

Melatonin is an endogenous molecule involved in many pathophysiological processes. In addition to the control of circadian rhythms, its antioxidant and neuroprotective properties have been widely described. Thus far, different bivalent compounds composed by a melatonin molecule linked to another neuroprotective agent were synthesized and tested for their ability to block neurodegenerative processes in vitro and in vivo. To identify a novel class of potential neuroprotective compounds, we prepared a series of bivalent ligands, in which a prototypic melatonergic ligand is connected to an imidazole-based H3 receptor antagonist through a flexible linker. Four imidazolyl-alkyloxy-anilinoethylamide derivatives, characterized by linkers of different length, were synthesized and their binding affinity for human MT1, MT2 and H3 receptor subtypes was evaluated. Among the tested compounds, 14c and 14d, bearing a pentyl and a hexyl linker, respectively, were able to bind to all receptor subtypes at micromolar concentrations and represent the first bivalent melatonergic/histaminergic ligands reported so far. These preliminary results, based on binding affinity evaluation, pave the way for the future development of new dual-acting compounds targeting both melatonin and histamine receptors, which could represent promising therapeutic agents for the treatment of neurodegenerative pathologies.

Topics: Binding Sites; Histamine Antagonists; Humans; Imidazoles; Ligands; Molecular Docking Simulation; Piperidines; Protein Binding; Protein Structure, Tertiary; Receptor, Melatonin, MT1; Receptor, Melatonin, MT2; Receptors, Histamine H3

Ligands targeting central histamine H3 receptors (H3Rs) for epilepsy might be a promising therapeutic approach. Therefore, the previously described and structurally strongly related imidazole-based derivatives belonging to carbamate class with high H3R in vitro affinity, in-vivo antagonist potency, and H3R selectivity profile were investigated on their anticonvulsant activity in maximal electroshock (MES)-induced and pentylenetetrazole (PTZ)-kindled seizure models in Wistar rats. The effects of systemic injection of H3R ligands 1-13 on MES-induced and PTZ-kindled seizures were screened and evaluated against the reference antiepileptic drug (AED) Phenytoin (PHT) and the standard histamine H3R inverse agonist/antagonist Thioperamide (THP) to determine their potential as new antiepileptic drugs. Following administration of the H3R ligands 1-13 (5, 10 and 15 mg/kg, ip) there was a significant dose dependent reduction in MES-induced seizure duration. The protective action observed for the pentenyl carbamate derivative 4, the most protective H3R ligand among 1-13, was significantly higher (P <0.05) than that of standard H3R antagonist THP, and was reversed when rats were pretreated with the selective H3R agonist R-(α)-methyl-histamine (RAMH) (10mg/kg), or with the CNS penetrant H1R antagonist Pyrilamine (PYR) (10mg/kg). In addition, subeffective dose of H3R ligand 4 (5mg/kg, ip) significantly potentiated the protective action in rats pretreated with PHT (5mg/kg, ip), a dose without appreciable protective effect when given alone. In contrast, pretreatment with H3R ligand 4 (10mg/kg ip) failed to modify PTZ-kindled convulsion, whereas the reference drug PHT was found to fully protect PTZ-induced seizure. These results indicate that some of the investigated imidazole-based H3R ligands 1-13 may be of future therapeutic value in epilepsy.

Topics: 1-Propanol; Animals; Anticonvulsants; Carbamates; Electroshock; Histamine Agonists; Histamine Antagonists; Imidazoles; Ligands; Rats; Rats, Wistar; Receptors, Histamine H3; Seizures

A series of 1-[[2-thiazol-5-yl-(2-aminoethyl)]-4-n-propyl]piperazine derivatives have been prepared and in vitro tested as H(3)-receptor antagonists (the electrically evoked contraction of the guinea pig jejunum). It appeared that by comparison of homologous pairs the 1-[[2-thiazol-5-yl-(2-methyl-2-phenylalkylaminoethyl)]-4-n-propyl]piperazine derivatives (4c1-4c3) have slightly higher activity than their 1-[2-thiazol-5-yl-(2-methyl-2-alkylaminoethyl)]-4-n-propylpiperazine analogues (4b1-4b3). In the 2-methylalkylamide series (4a1-4a3) a somewhat lower activity was observed. The most potent compound of the series is the 1-[2-thiazol-5-yl-(2-methyl-2-phenylpropylaminoethyl)]-4-n-propylpiperazine (4c2) with pA(2)=8.27 (its alkyl analogue (4b2) showed pA(2)=7.53 and the corresponding amide (4a2) displayed pA(2)=7.36). Selected compounds (4b1, 4b2, 4c1 and 4c2) were also tested (in vitro) for H(1) antagonistic effects in vitro applying standard methods (guinea pig ileum). None showed any H(1) antagonistic activity (pA(2)<4).

Topics: Animals; Guinea Pigs; Histamine H1 Antagonists; Histamine H3 Antagonists; Imidazoles; Jejunum; Male; Piperazine; Piperazines; Receptors, Histamine H3; Structure-Activity Relationship

A series of imidazole-containing (non-)chiral carbamates were tested at human histamine H(3) receptor (H(3)R). All compounds displayed K(i) values below 100 nM. A trend for a stereoselectivity at human H(3)R was observed for the chiral alpha-branched ligands. Selected compounds were also tested at human histamine H(4) receptor and showed moderate to weak affinities (118-1460 nM).

Topics: Carbamates; Drug Design; Humans; Imidazoles; Molecular Structure; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H3; Receptors, Histamine H4; Stereoisomerism; Structure-Activity Relationship