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The synthesis of some alkyl, aryl thioureas and aryl ureas starting from 5-trans-(3-aminopropoxy)-1,2,3,3-tetramethyl-2-azabicyclo[2.2.2]octane is described. Some thioureas showed a remarkable antiarrhythmic activity besides a weak hypotensive effect in rats and, like some ureas, infiltration anesthesia in mice.
Non-insulin-dependent diabetes mellitus (NIDDM) is associated with an increased risk of macro- and microvascular degenerative complications. Gliclazide is a second generation sulfonylurea that is widely used in the treatment of type II diabetes mellitus. Its hypoglycemic activity is well documented. In addition to its metabolic effects, gliclazide has beneficial effects on the hemobiological abnormalities of NIDDM. These effects are mediated by the azabicyclo-octyl ring grafted on to its aulfonylurea core. Numerous studies have demonstrated that gliclazide reduces platelet hyperadhesion and platelet hyperaggregability. These actions have been extensively confirmed in diabetic patients over periods of up to 3 years. With regard to platelet functions, several groups have demonstrated a significant reduction in serum and intraplatelet beta thromboglobulin and thromboxane B2. In animal models, in-vitro and in-vivo gliclazide stimulates endothelial prostacyclin synthesis. The beneficial effects of the compound on thromboxane/prostacyclin balance have been recently confirmed in type II diabetic patients after a 3-month treatment period. Concerning fibrinolysis, gliclazide restores low plasminogen activity to normal in NIDDM patients previously treated with first-generation sulfonyl-ureas. Gliclazide increases fibrinolytic potential by increasing endothelial cell tissue plasminogen activator and pre-kallikrein activity. More recent studies suggest that gliclazide may have effects on fibrin network structure, rendering the fibrin more amenable to fibrinolysis. Finally, it has been shown that gliclazide has a potent free-radical-scavenging activity in vitro. This property has been recently confirmed in vivo in type II diabetic patients and may suggest that platelet reactivity and oxidative stress are related in these patients.(ABSTRACT TRUNCATED AT 250 WORDS)
(+/-)-Epibatidine, exo-2-(6-chloro-3-pyridyl)-7-azabicyclo-[2.2.1] heptane, is a novel, potent analgesic agent that acts through nicotinic acetylcholine receptor (nAChR) mechanisms. This study sought to establish whether (+/-)-epibatidine, like (-)-nicotine, also displays a wide diversity of behavioral responses that are known to be elicited by nAChR activation or whether it demonstrates subtype selectivity for its interactions with nAChRs.(+/-)-Epibatidine displaced [3H](-)-cytisine binding to the alpha 4 beta 2 nAChR subtype in rat brain membranes with high affinity (Ki, 43 pM). The compound was approximately 5000-fold less potent (Ki = 230nM) in the displacement of [125I] alpha-bungarotoxin binding from the alpha-bungarotoxin-sensitive nAChR subtype present in rat brain but was a potent inhibitor (Ki, 2.7 nM) of [125I] alpha-bungarotoxin binding to the nAChR subtype in Torpedo electroplax, which is similar to that present in the neuromuscular junction. Functionally, (+/-)-epibatidine enhanced 86Rb+ flux in IMR 32 cells with an EC50 value of 7 nM. It was some 3000-fold more potent than (-)-nicotine (EC50 value, 21,000 nM) and was approximately 150-fold more potent (EC50 value, 0.4 nM) than (-)-nicotine (EC50 value = 60 nM) in increasing [3H]dopamine release from rat striatal slices. Remarkably, (+/-)-epibatidine was 40% to 50% more efficacious than (-)-nicotine in both functional assays. Both functional effects were blocked by the nAChR channel blocker, mecamylamine (100 microM). (+/-)-Epibatidine was 300 to 1000 times more potent than (-)-nicotine in the reduction of body temperature and locomotor activity in mice.(ABSTRACT TRUNCATED AT 250 WORDS)
Sabcomeline, (SB-202026 [R-(Z)-alpha-(methoxyimino)-1 -azabicyclo [2.2.2] octane-3-acetonitrile]), a functionally selective muscarinic M1 receptor partial agonist, was tested in rats trained to perform a delayed, reinforced alternation task in a T maze, a test of short-term spatial memory. For comparison the cholinesterase inhibitor tacrine (THA-9-amino- 1,2,3,4-tetrahydroaminoacridine) and the non-selective muscarinic receptor agonist RS86 (2-ethyl-8-methyl-2,8 diazospiro [4.5]-decane-1,3-dione hydrobromide) were also tested and all three compounds were also compared using a conditioned taste aversion (CTA) task. Sabcomeline (0.001-1.0 mg/kg i.p.) significantly reversed the T-maze choice accuracy deficit induced by a 20-s delay at 0.03 and 0.1 mg/kg. RS86 (0.1-3.0 mg/kg i.p.) reversed the deficit at 1.0 mg/kg and THA (0.1-3.0 mg/kg i.p.) had no effect at any dose. All three compounds induced conditioned taste aversion with minimum effective doses (MED) of 0.3, 1.0 and 3.0 mg/kg, respectively. The results show that sabcomeline reverses delay induced deficits in T-maze choice accuracy in a rewarded alternation task at doses approximately 10 times lower than those required to induce conditioned taste aversion. RS86 was equipotent in both tests. These data support the findings of clinical studies which have shown that SB-202026 provides significant symptomatic improvement in patients with probable Alzheimer's disease at doses which do not induce cholinergic side effects.
1. L-689,660, 1-azabicyclo[2.2.2]octane, 3-(6-chloropyrazinyl)maleate, a novel cholinomimetic, demonstrated high affinity binding (pKD (apparent) 7.42) at rat cerebral cortex muscarinic receptors. L-689,660 had a low ratio (34) of pKD (apparent) values for the displacement of binding of the antagonist ([3H]-N-methylscopolamine ([3H]-NMS) compared with the displacement of the agonist [3H]-oxotremorine-M ([3H]-Oxo-M), in rat cerebral cortex. Low NMS/Oxo-M ratios have been shown previously to be a characteristic of compounds that are low efficacy partial agonists with respect to stimulation of phosphatidyl inositol turnover in the cerebral cortex. 2. L-689,660 showed no muscarinic receptor subtype selectivity in radioligand binding assays but showed functional selectivity in pharmacological assays. At M1 muscarinic receptors in the rat superior cervical ganglion, L-689,660 was a potent (pEC50 7.3 +/- 0.2) full agonist in comparison with (+/-)-muscarine. At M3 receptors in the guinea-pig ileum myenteric plexus-longitudinal muscle or in trachea, L-689,660 was again a potent agonist (pEC50 7.5 +/- 0.2 and 7.7 +/- 0.3 respectively) but had a lower maximum response than carbachol. In contrast L-689,660 was an antagonist at M2 receptors in guinea-pig atria (pA2 7.2 (95% confidence limits 7, 7.4)) and at muscarinic autoreceptors in rat hippocampal slices. 3. The putative M1-selective muscarinic agonist, AF102B (cis-2-methylspiro-(1,3-oxathiolane 5,3')-quinuclidine hydrochloride) was found to have a profile similar to L-689,660 but had up to 100 times less affinity in binding and functional assays.RS-86 (2-ethyl-8-methyl-2,8-diazospiro[4,5]decan 1,3-dionehydrochloride) also had lower affinity than L-689,660, and had no binding selectivity for muscarinic receptor subtypes. RS-86 had a higher NMS/Oxo-M ratio than L-689,660 and was a full agonist at MI,M2 and M3 receptors in the functional pharmacological assays.4. The functional selectivity of L-689,660 in muscarinic pharmacological assays is consistent with the effects of a low efficacy partial agonist in tissues with different effective receptor reserves.
Pharmacological studies were performed to investigate the interaction of SC-27166 (2-[3-(5-methyl-1,3,4--oxadiazol-2-yl)-3,3-diphenylpropyl]-2-azabicyclo[2.2.2]octane), a new antidiarrheal agent, with opiate receptor sites in vitro and in vivo. Morphine, loperamide and SC-27166 inhibited the binding of [3H]naloxone to homogenates of guinea-pig brain and myenteric plexus and the inhibition was diminished in the presence of 100 mM Na+. Unlike that of morphine and [3H]naloxone itself, the binding of loperamide and SC-27166 was complex and Scatchard plots indicated the presence of low and high affinity sites for both compounds. Morphine, loperamide and SC-27166 inhibited the contractions of electrically driven longitudinal muscle from guinea-pig ileum and naloxone antagonized these effects. In the anesthetized dog, i.v. administration of morphine and SC-27166 enhanced the contractile activity of circular muscle in proximal and distal duodenum and distal ileum but duodenal longitudinal muscle was relaxed; these effects were completely reversed by subsequent administration of naloxone. In the rat, p.o. administration of loperamide and SC-27166 inhibited intestinal propulsion at doses considerably lower than were necessary to produce activity in the hot plate test; this specificity of action was not seen with morphine. In the rat, p.o. administration of loperamide and SC-27166 inhibited diarrhea at doses considerably lower than were necessary to produce withdrawal symptoms. The authors concluded that both loperamide and SC-27166 are specific antidiarrheal agents that produce both their central and antidiarrheal effects by binding to opiate receptor sites.
The nephrotoxicity of 1-[2-carboxy-8-oxo-7-(2-thienylacetamido)-5-thio-1-azabicyclo[4.2.0]oct-2-en-3- yl]methyl-pyridinium hydroxide (cephaloridine, Glaxoridin) in mice was investigated histopathologically in a series of 14 experiments. Using the PAS-reaction lesion formation consisting of epithelial desquamation in the tubuli contorti proximales, coarse cytoplasmic granulation of the tubuli recti proximales epithelium and hyaline cast formation was detected. Regeneration of the tubular epithelium followed subsequently. Optimal lesion formation was detected when mice were given two s.c. injections of an aqueous solution of the compound and the post mortem was carried out two days later. B5D2F1 hybrid mice were more sensitive than NMRI mice. However, a preexperimental acclimatisation period of at least ten days was necessary to obtain reproducible results.
A series of 8-beta-acyloxy-3-phenethyl-3-azabicyclo[3.2.1]octane and its N-endo methiodides were synthesized and studied by 1H and 13C NMR spectroscopy, and the crystal structure of 8-beta-p-chlorobenzoyloxy-3-phenethyl-3-azabicyclo[3.2.1]octane methiodide (2c) was determined by X-ray diffraction. In CDCl3 solution, 1b-1e display the same preferred conformation. The cyclopentane and piperidine rings adopt an envelope conformation flattened at C-8 and a distorted chair conformation puckered at C-8 and flattened at N-3, respectively, with the N-substituent in the equatorial position with respect to the piperidine ring. In all cases, methylation takes place from the endo position. The ability of the title compounds to antagonize the acetylcholine-induced contraction of guinea pig ileum is also reported. An initial structure-activity relationship is proposed.
Antagonists of 5HT3 receptors are clinically effective in treating nausea and emesis associated with certain oncolytic drugs, including cisplatin. Moreover, these agents may be useful in pharmacological management of several central nervous system disorders, including anxiety, schizophrenia, dementia, and substance abuse. Our studies on aroyltropanamides led to the discovery that dihydrobenzofuranyl esters and amides are potent 5HT3 receptor antagonists. Simple benzoyl derivatives of tropine and 3 alpha-aminotropane possessed weak 5HT3 receptor antagonist activity, as judged by blockade of bradycardia produced by iv injection of serotonin (5HT) to anesthetized rats. Within this series, use of benzofuran-7-carboxamide as the aroyl moiety led to a substantial increase of 5HT3 receptor affinity. The optimal 5HT3 receptor antagonist identified via extensive SAR studies was endo-5-chloro-2,3-dihydro-2,2-dimethyl-N-(8-methyl-8-azabicyclo[3.2.1]oc t- 3-yl)-7-benzofurancarboxamide (Z)-2-butenedioate (zatosetron maleate). The 7-carbamyl regiochemistry, dimethyl substitution, chloro substituent, and endo stereochemistry were all crucial elements of the SAR. Zatosetron maleate was a potent antagonist of 5HT-induced bradycardia in rats (ED50 = 0.86 micrograms/kg i.v.). Low oral doses of zatosetron (30 micrograms/kg) produced long-lasting antagonism of 5HT3 receptors, as evidenced by blockade of 5HT-induced bradycardia for longer than 6 h in rats. Moreover, this compound did not produce hemodynamic effects after i.v. administration to rats, nor did it block carbamylcholine-induced bradycardia in doses that markedly blocked 5HT3 receptors. Thus, zatosetron is a potent, selective, orally effective 5HT3 receptor antagonist with a long duration of action in rats.
A newly synthesized agonist for muscarinic acetylcholine (ACh) receptors CS-932, (R)-3-(3-iso-xazoloxy)-1-azabicyclo-[2.2.2]octane hydrochloride, showed a relatively higher affinity for M1 than M2 receptors expressed in Chinese hamster ovary (CHO)-cells in comparison with ACh. CS-932 elevated the intracellular Ca2+ level only in M1-CHO cells, although ACh increased the level in both M1- and M3-CHO cells. CS-932 and ACh reduced forskolin-stimulated accumulation of cAMP in M2-CHO cells by 20% and 80%, respectively. This neurochemical profile of CS-932 indicates that the compound can activate M1-receptor-mediated functions selectively. CS-932 increased firing of cholinoceptive neurons in rat hippocampal slices, and this excitation was antagonized by pirenzepine, but not by AF-DX 116. CS-932 increased awake and decreased slow wave sleep episodes of daytime EEG in free-moving rats. It counteracted scopolamine-induced slow waves in rat cortical EEG. CS-932 also increased the power of alpha- and beta-waves, but decreased delta-wave of the cortical EEG in anesthetized monkeys. It ameliorated scopolamine-induced impairment of working memory in rats. Orally administered CS-932 had the best penetration into the brain among the muscarinic agonists tested and caused the least salivary secretion among the cholinomimetics examined. These results indicate that CS-932 has potential as a cognitive enhancer with fewer side effects in therapy for Alzheimer disease.
Dibenzylformamide was treated with cyclohexylmagnesium bromide in the presence of either titanium tetraisopropoxide or methyltitanium triisopropoxide and a variety of cyclic and acyclic alkenes and alkadienes to give new mono- and disubstituted as well as bicyclic dialkylcyclopropylamines (Tables 1-3) in yields ranging from 18 to 90 % (in most cases around 55 %). 3-Benzyl-6-(N,N-dibenzylamino)-3-azabicyclo[3.1.0]hexane (10 a) and the orthogonally bisprotected 3-tert-butoxycarbonyl-6-(N,N-dibenzyl)-3-azabicyclo[3.1.0]hexane (10 d) as well as the analogous 6-(N,N-dibenzylamino)bicyclo[3.1.0]hexane (12) were obtained as pure exo diastereomers in particularly high yields (87, 90, and 88 %, respectively) from N-benzylpyrroline (15 a), N-Boc-pyrroline (15 d; Boc=tert-butyloxycarbonyl) and cyclopentene (19). 1,3-Butadiene (52) and substituted 1,3-butadienes were also aminocyclopropanated quite well to give 2-ethenylcyclopropylamines in good yields (51-64 %). Except for alkenyl- and aryl-substituted compounds, N,N-dibenzylcyclopropylamines can be debenzylated by catalytic hydrogenation to the primary cyclopropylamines as demonstrated for 10 a and 10 d to yield the fully deprotected 10 e (93 %) and mono-Boc-protected 10 f (98 %), respectively. The latter are interesting templates for combinatorial syntheses of libraries of small molecules with a well defined distance of 4.3 A between two nitrogen atoms.
Squalene synthase catalyzes the reductive dimerization of two molecules of farnesyl pyrophosphate to form squalene and is the first committed step in sterol synthesis. A specific inhibitor of squalene synthase would inhibit cholesterol biosynthesis but not prevent the formation of other products of the isoprenoid pathway, such as dolichol and ubiquinone. RPR 107393 [3-hydroxy-3-[4-(quinolin-6-yl)phenyl]-1-azabicyclo[2-2-2]octane dihydrochloride] and its R and S enantiomers are potent inhibitors of rat liver microsomal squalene synthase, with IC50 values of 0.6 to 0.9 nM. One hour after oral administration to rats, RPR 107393 inhibited de novo [14C]cholesterol biosynthesis from [14C]mevalonate in the liver with an ED50 value of 5 mg/kg. Diacid metabolites of [14C]farnesyl pyrophosphate were identified after acid treatment of the livers of these animals. These results support in vitro data demonstrating that these compounds are inhibitors of squalene synthase. In rats, RPR 107393 (30 mg/kg p.o. b.i.d. for 2 days) reduced total serum cholesterol by < or = 51%. In the same paradigm, the HMG-CoA reductase inhibitor lovastatin failed to lower serum cholesterol in rats. In marmosets, RPR 107393 (20 mg/kg b.i.d.) reduced plasma cholesterol concentration by 50% after 1 week of administration; this was greater than the reduction observed with lovastatin or pravastatin, neither of which produced > 31% reduction in plasma cholesterol when administered for 1 week at a dose of 50 mg/kg b.i.d. The R and S enantiomers of RPR 107393 (20 mg/kg p.o. q.d. for 7 days) reduced plasma low density lipoprotein cholesterol by 50% and 43%, respectively, whereas high density lipoprotein cholesterol was unchanged. In summary, RPR 107393 is a potent inhibitor of squalene synthase. It is an orally effective hypocholesterolemic agent in rats and marmosets that has greater efficacy than lovastatin or pravastatin in the marmoset.
Eight analogs of the fentanyl-type analgesics, in which the piperidine ring is restricted into a boat conformation, were evaluated for analgesic activity. All analogs were less active than fentanyl, but interesting conformational and structural relationships were observed. Results of the study are discussed.
A series of 4-hydroxy-3-quinolinecarboxylic acid derivatives (6) and 4-hydroxy-2-oxo-1,2-dihydro-3-quinolinecarboxylic acid derivatives (7) were designed and synthesized as 5-HT3 receptor antagonists. Molecular modeling studies suggested that the 3-carbonyl moiety in 6 was almost coplanar to the plane of an aromatic ring, but in 7 there was a 30 degrees deviation. 4-Hydroxy substitution in quinoline derivatives enhanced affinity for the 5-HT3 receptors, and endo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-4-hydroxy-3- quinolinecarboxamide (6f) exhibited the most potent activity in the Bezold-Jarisch (B-J) reflex test (ED50 = 0.1 micrograms/kg, iv) among quinoline derivatives 6. Although 4-hydroxy-2-oxo-1,2-dihydro-3-quinolinecarboxamide derivatives (7a) exhibited higher affinity (e.g., 7d: Ki = 0.48 nM) for the 5-HT3 receptors than ondansetron (Ki = 7.6 nM) or granisetron (Ki = 2.1 nM), these amides showed less potent activity in the B-J reflex test than the reference compounds. Interestingly, the ester derivatives 7c, 7f, and 7h eliminated affinity for the 5-HT3 receptors. These unusual structure-activity relationships and the deviation of the 3-carbonyl moiety from the plane of an aromatic ring suggest that the active conformation of 7a might be different from the proposed one for the preceding 5-HT3 antagonists. Thus, 6f was chosen for further studies. No receptor binding for a variety of ligands was significantly antagonized by 6f. Comparing the ratios of the ED50 value in the B-J reflex test (rat, iv) with the LD50 value in acute lethal toxicity (mouse, iv), 6f was proved to have a 600-fold wider margin of safety than ondansetron. Compound 6f dose-dependently attenuated both the incidence and frequency of emetic episodes induced by cisplatin in the dog (ED50 = 14 micrograms/kg, iv) more potently than ondansetron (ED50 = 210 micrograms/kg, iv). Compound 6f (KF-20170) is now under further investigation as a drug for treating gastrointestinal disorder.
To explore the role of ester groups in the neuromuscular blocking (NMB) property of various quaternary ammonium tropinesters, we have synthesized and pharmacologically evaluated twenty bisquaternary ammonium derivatives where two tropane (I), 3alpha-hydroxytropane (II), or 3-oxotropane (III) moieties were connected on their nitrogen atoms with a polymethylene chain of C3-C12 length. The rank order of potency of these agents in the rat (evoked EMG responses of the ant. tibial muscle) was: I, II, and III. Most potent were the longer chain (e.g. C10-C12) compounds of series I, yet they were inferior to bisquaternary ammonium tropinester derivatives (e.g. N,N'-polymethylene bisquaternary tropinesters, or bisquaternary derivatives of dicarboxylic acid tropinesters). Although some of the agents (series I and II) showed a rapid onset and short duration of action-profile, they also exhibited cardiovascular side effects (e.g. cardiac vagal block and blood pressure changes). In the design of new NMB agents of rapid onset and short duration of action the presence of different ester groups in addition to an azabicyclo ring system (e.g. tropane), seems to be essential.
(5R,6R)-6-(3-butylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[3.2.1]octane) (BuTAC) is a novel, selective muscarinic receptor ligand with partial agonist mode of action at muscarinic M2 and M4 and antagonist mode of action at M1, M3 and M5 receptor subtypes in cloned cell lines. BuTAC exhibits functional dopamine receptor antagonism despite its lack of affinity for dopamine receptors, and parasympathomimetic effects in mice are produced only at doses well beyond the doses exhibiting the antipsychotic-like effects. In the present study we investigated the effects of BuTAC and the antipsychotic compounds clozapine, sertindole and olanzapine using one trial passive avoidance with mice as a model of learning and memory. Pharmacologically relevant doses of BuTAC and reference antipsychotics were identified, based on inhibition of apomorphine-induced climbing in mice as an assay measuring antidopaminergic potency. When ratios between the minimum effective dose (MED) for impairment of retention in passive avoidance and the MED for inhibition of apomorphine-induced climbing were calculated, BuTAC displayed a high ratio of >10, compared with clozapine (0.3), sertindole (3) and olanzapine (3). These data suggest that BuTAC is a potential novel antipsychotic which may have favourable effects on aspects of learning and memory.
A novel method for the epimerization of endo-2-(6-chloro-3-pyridyl)-7-azabicyclo[2.2.1]heptan-3-one (12) on silica gel was developed and used as the key step to synthesize functionalized analogues of epibatidine which were evaluated for their nicotine receptor subtype selectivity in binding studies.