ABSTRACT
Histamine 3 (H(3)) receptors are distributed throughout the brain and regulate histamine as well as the activity of other neurotransmitters including acetylcholine (ACh). Impaired ACh neurotransmission is associated with deficits of cognitive-related functioning in many species including humans. The goal of these studies was to evaluate the behavioral and neurochemical effects of JNJ-10181457, a selective non-imidazole histamine H(3) receptor antagonist, in rats. The pharmacokinetic profile and receptor occupancy of JNJ-10181457 were tested. The efficacy of JNJ-10181457 was evaluated, acutely, in the imetit-induced water licking model, delayed non-matching to position (DNMTP) task and microdialysis studies. In addition, the effects of repeated administration of JNJ-10181457 were evaluated in the reversal learning task. A single administration of JNJ-10181457 (10 mg/kg, i.p.) resulted in significant plasma and brain exposure and maximal H(3) receptor occupancy. In addition, JNJ-10181457 reversed imetit-induced water licking, similarly to thioperamide (10 mg/kg, i.p.). In the DNMTP task, scopolamine (0.06 mg/kg, i.p.) significantly decreased percentage correct responding. These effects were significantly reversed by JNJ-10181457 (10 mg/kg, i.p.) and also by donepezil (1 mg/kg, i.p.), an acetylcholinesterase inhibitor, and were associated with normalization of ACh neurotransmission in the cortex. Repeated administration of JNJ-10181457 (10 mg/kg, i.p.) significantly increased percentage correct responding in the reversal learning task. Treatment discontinuation was not associated with rebound effects on cognition. These results indicate that selective blockade of histamine H(3) receptors might have therapeutic utility for the treatment of working memory deficits and learning disorders, especially those in which ACh neurotransmission is compromised.
Subject(s)
Acetylcholine/metabolism , Cognition/drug effects , Histamine Antagonists/pharmacology , Morpholines/pharmacology , Nootropic Agents/pharmacology , Piperidines/pharmacology , Receptors, Histamine H3/drug effects , Synaptic Transmission/drug effects , Animals , Anticonvulsants/pharmacology , Brain/drug effects , Brain/metabolism , Cholinesterase Inhibitors/pharmacology , Cognition/physiology , Conditioning, Operant/drug effects , Donepezil , Drinking Behavior/drug effects , Drinking Behavior/physiology , Drug Evaluation, Preclinical , Histamine Agonists/pharmacology , Histamine Antagonists/pharmacokinetics , Imidazoles/pharmacology , Indans/pharmacology , Learning/drug effects , Learning/physiology , Microdialysis , Morpholines/pharmacokinetics , Muscarinic Antagonists/pharmacology , Nootropic Agents/pharmacokinetics , Piperidines/pharmacokinetics , Rats , Rats, Sprague-Dawley , Scopolamine/pharmacology , Synaptic Transmission/physiology , Thiourea/analogs & derivatives , Thiourea/pharmacologyABSTRACT
A novel series of imidazole containing histamine H(3) receptor ligands were investigated and found to be potent functional antagonists. After improving the stability of these molecules towards liver microsomes, these compounds were found to have no appreciable affinity for CYP P450s. Subsequent in vivo experiments showed significant brain uptake of (4-chloro-phenyl)-[2-(1-isopropyl-piperidin-4-ylmethoxy)-3-methyl-3H-imidazol-4-yl]-methanone 22.
Subject(s)
Blood-Brain Barrier/drug effects , Brain/drug effects , Chemistry, Pharmaceutical/methods , Histamine H3 Antagonists/chemistry , Histamine H3 Antagonists/chemical synthesis , Imidazoles/chemistry , Animals , Brain/metabolism , Drug Design , Drug Evaluation, Preclinical , Guinea Pigs , Histamine H3 Antagonists/metabolism , Humans , Ligands , Models, Chemical , Protein Binding , Rats , Structure-Activity RelationshipABSTRACT
Aplysamine-1 (1), a marine natural product, was synthesized and screened for in vitro activity at the human and rat histamine H3 receptors. Aplysamine-1 (1) was found to possess a high binding affinity for the human H3 receptor (Ki = 30+/-4 nM). Synthetic analogs of 1, including des-bromoaplysamine-1 (10) and dimethyl-{2-[4-(3-piperidin-1-yl-propoxy)-phenyl]-ethyl}-amine (13), were potent H3 antagonists.