ABSTRACT
Adenosine kinase (AK) is the primary enzyme responsible for adenosine metabolism. Inhibition of AK effectively increases extracellular adenosine concentrations and represents an alternative approach to enhance the beneficial actions of adenosine as compared to direct-acting receptor agonists. Clitocine (3), isolated from the mushroom Clitocybe inversa, has been found to be a weak inhibitor of AK. We have prepared a number of analogues of clitocine in order to improve its potency and demonstrated that 5'-deoxy-5'-amino-clitocine (7) improved AK inhibitory potency by 50-fold.
Subject(s)
Adenosine Kinase/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Pyrimidine Nucleosides/chemistry , Pyrimidine Nucleosides/pharmacology , Animals , Biochemistry/methods , Drug Design , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemical synthesis , Inhibitory Concentration 50 , Rats , Structure-Activity RelationshipABSTRACT
Analogs of compound 1 with a variety of azacycles and heteroaryl groups were synthesized. These analogs exhibited Ki values ranging from 0.15 to > 10,000 nM when tested in vitro for cholinergic channel receptor binding activity (displacement of [3H](-) cytisine from whole rat brain synaptic membranes).
Subject(s)
Cholinergic Agonists/pharmacology , Animals , Brain/metabolism , Cholinergic Agonists/chemistry , Cholinergic Agonists/metabolism , Ethers/chemistry , Rats , Structure-Activity RelationshipABSTRACT
Nitric oxide (NO.) is an important biomodulator of many physiological processes. The inhibition of inappropriate production of NO. by the isoforms of nitric oxide synthase (NOS) has been proposed as a therapeutic approach for the treatment of stroke, inflammation, and other processes. In this study, certain 2-nitroaryl-substituted amino acid analogues were discovered to inhibit NOS. Analogues bearing a 5-methyl substituent on the aromatic ring demonstrated maximal inhibitory potency. For two selected inhibitors, investigation of the kinetics of the enzyme showed the inhibition to be competitive with l-arginine. Additionally, functional NOS inhibition in tissue preparations was demonstrated.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Isoenzymes/antagonists & inhibitors , Neurons/drug effects , Nitric Oxide Synthase/antagonists & inhibitors , Nitro Compounds/chemical synthesis , Ornithine/chemical synthesis , Acetylcholine/pharmacology , Animals , Cerebellum/cytology , Cerebellum/drug effects , Cerebellum/enzymology , Cerebellum/metabolism , Cyclic GMP/antagonists & inhibitors , Endothelium, Vascular/enzymology , Endothelium, Vascular/physiology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , In Vitro Techniques , Kinetics , Muscle Relaxation/drug effects , Neurons/enzymology , Nitro Compounds/chemistry , Nitro Compounds/pharmacology , Ornithine/analogs & derivatives , Ornithine/chemistry , Ornithine/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
Analogs of A-98593 (1) and its enantiomer ABT-594 (2) with diverse substituents on the pyridine ring were prepared and tested for affinity to nicotinic acetylcholine receptor binding sites in rat brain and for analgesic activity in the mouse hot plate assay. Numerous types of modifications were consistent with high affinity for [3H]cytisine binding sites. By contrast, only selected modifications resulted in retention of analgesic potency in the same range as 1 and 2. Analogs of 2 with one or two methyl substituents at the 3-position of the azetidine ring also were prepared and found to be substantially less active in both assays.
Subject(s)
Analgesics, Non-Narcotic/chemical synthesis , Analgesics, Non-Narcotic/pharmacology , Azetidines/chemical synthesis , Azetidines/pharmacology , Nicotinic Agonists/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , Receptors, Nicotinic/metabolism , Alkaloids/metabolism , Analgesics, Non-Narcotic/metabolism , Animals , Azetidines/chemistry , Azetidines/metabolism , Azocines , Binding Sites , Brain/metabolism , Mice , Nicotinic Agonists/chemistry , Pain Measurement/drug effects , Pyridines/chemistry , Pyridines/metabolism , Quinolizines , Rats , Receptors, Nicotinic/drug effects , Stereoisomerism , Structure-Activity Relationship , TritiumABSTRACT
ABT-089 [2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride], a novel ligand at neuronal nicotinic acetylcholine receptors with reduced adverse effects and improved oral bioavailability relative to (-)-nicotine, was tested in a variety of cognitive tests in rats and monkeys. Administered acutely, ABT-089 only marginally improved the spatial discrimination water maze performance of septal-lesioned rats. However, more robust improvement (45% error reduction on the last training day) was observed when ABT-089 was administered continuously via subcutaneous osmotic pumps (minimum effective dose: 1.3 micromol/kg/day). Continuous infusion of (-)-nicotine produced comparable improvement in the spatial discrimination water maze performance of septal-lesioned rats, but a 40-fold higher dose of (-)-nicotine was required (62 micromol/kg/day). Continuous infusion of ABT-089 to aged rats enhanced spatial learning in a standard Morris water maze, as indexed by spatial bias exhibited during a probe trial conducted after 4 days of training, but not when they were subsequently trained in a two-platform spatial discrimination water maze. The compound induced a small impairment in young rats on the standard water maze, but not on the two-platform task. A probe trial conducted after additional training in the standard water maze revealed no age or drug effects. ABT-089 did not affect performance of either the aged or young rats during inhibitory (passive) avoidance training. Also, continuous infusion of ABT-089 did not affect responses to acoustic startle or prepulse inhibition of acoustic startle in young, aged or septal-lesioned rats and did not affect locomotor activity in either sham-lesioned or septal-lesioned rats. In monkeys, acute administration of ABT-089 modestly improved the delayed matching-to-sample performance of mature, adult monkeys and more robustly improved performance in aged monkeys. Improved performance in the aged monkeys was restricted to the longest delay intervals and was not accompanied by changes in response latencies.
