SCH 57790, a selective muscarinic M(2) receptor antagonist, releases acetylcholine and produces cognitive enhancement in laboratory animals.

The present studies were designed to assess whether the novel muscarinic M(2) receptor antagonist 4-cyclohexyl-alpha-[4[[4-methoxyphenyl]sulphinyl]-phenyl]-1-piperazineacetonitrile (SCH 57790) could increase acetylcholine release in the central nervous system (CNS) and enhance cognitive performance in rodents and nonhuman primates. In vivo microdialysis studies show that SCH 57790 (0.1-10 mg/kg, p.o.) produced dose-related increases in acetylcholine release from rat hippocampus, cortex, and striatum. SCH 57790 (0.003-1.0 mg/kg) increased retention times in young rat passive avoidance responding when given either before or after training. Also, SCH 57790 reversed scopolamine-induced deficits in mice in a passive avoidance task. In a working memory operant task in squirrel monkeys, administration of SCH 57790 (0.01-0.03 mg/kg) improved performance under a schedule of fixed-ratio discrimination with titrating delay. The effects observed with SCH 57790 in behavioral studies were qualitatively similar to the effects produced by the clinically used cholinesterase inhibitor donepezil, suggesting that blockade of muscarinic M(2) receptors is a viable approach to enhancing cognitive performance.

Muscarinic agonists and antagonists in the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by cognitive impairment and personality changes. The development of drugs for the treatment of the cognitive deficits of AD has focused on agents which counteract loss in cholinergic activity. Although symptoms of AD have been successfully treated with acetylcholinesterase inhibitors (tacrine, donepezil. rivastigmine, galanthamine), limited success has been achieved with direct M1 agonists, probably due to their lack of selectivity versus other muscarinic receptor subtypes. Muscarinic M2 antagonists have been reported to increase synaptic levels of acetylcholine after oral administration to rats (e.g. BIBN-99, SCH-57790), but their selectivity versus other muscarinic receptor subtypes is modest. Exploration of a series of piperidinylpiperidines has yielded the potent and selective M2 antagonist SCH-217443. This antagonist has excellent bioavailability in rats and dogs and shows activity in a rat model of cognition.

Diphenyl sulfoxides as selective antagonists of the muscarinic M2 receptor.

Structure activity studies on [4-(phenylsulfonyl)phenyl]methylpiperazine led to the discovery of 4-cyclohexyl-alpha-[4-[[4-methoxyphenyl(S)-sufinyl]phenyl]-1-pi perazineacetonitrile, 1, an M2 selective muscarinic antagonist. Affinity at the cloned human M2 receptor was 2.7 nM; the M1/M2 selectivity is 40-fold.

SCH 57790: a novel M2 receptor selective antagonist.

As a decrease in cholinergic neurons has been observed in Alzheimer's Disease (AD), therapeutic approaches to AD include inhibition of acetylcholinesterase to increase acetylcholine levels. Evidence suggests that acetylcholine release in the CNS is modulated by negative feedback via presynaptic M2 receptors, blockade of which should provide another means of increasing acetylcholine release. Structure-activity studies of [4-(phenylsulfonyl)phenyl]methylpiperazines led to the synthesis of 4-cyclohexyl-alpha-[4-[[4-methoxyphenyl]sulfinyl]-phenyl]-1-piperazin eacetonitrile. This compound, SCH 57790, binds to cloned human M2 receptors expressed in CHO cells with an affinity of 2.78 nM; the affinity at M1 receptors is 40-fold lower. SCH 57790 is an antagonist at M2 receptors expressed in CHO cells, as the compound blocks the inhibition of adenylyl cyclase activity mediated by the muscarinic agonist oxotremorine. This compound should be useful in assessing the potential of M2 receptor blockade for enhancement of cognition.

Cardiomegaly on chest x-ray: prognostic implications from a ten-year cohort study of elderly subjects: a report from the Bronx Longitudinal Aging Study.

This report is from a 10-year cohort study of community-dwelling elderly men and women. Mean age at the time of entry into the study was 79 years. Annual chest x-ray studies were performed, and data are presented regarding prevalence, incidence, and prognosis of cardiomegaly. Cardiomegaly was defined as a transverse diameter of the cardiac silhouette greater than or equal to 50% of the transverse diameter of the chest (increased cardiothoracic ratio). At the time of entry into the study 110 subjects (23%) had cardiomegaly. After 10 years, 51% of the subjects with cardiomegaly at baseline died compared with 33% of the subjects without cardiomegaly (mortality rate = 9.1 vs 4.8/100 person-years respectively; p = 0.014). Cardiovascular disease incidence was also higher for those with preexisting cardiomegaly at baseline (rate 9.1 vs 6.1/100 person-years; p = 0.0001). According to the Cox proportional hazards regression analysis, age, cardiomegaly, diabetes, and prior evidence of myocardial infarction were independent predictors for death in this cohort. Similarly, the best predictive variables for cardiovascular disease were age, diabetes, prior evidence of myocardial infarction, and cigarette smoking. Of the 359 subjects without cardiomegaly at baseline, 108 (30%) showed evidence of new cardiomegaly, and their risk of cardiovascular disease was 1.8 times that of subjects whose test results were negative for cardiomegaly throughout the study (p = 0.003). Thus cardiomegaly, as defined by an increased cardiothoracic ratio on x-ray films, irrespective of cause, is associated with a poor prognosis in very elderly men and women.

Isobenzofurans as conformationally constrained miconazole analogues with improved antifungal potency.

A series of halogen-substituted isobenzofuran analogues was synthesized, which represented conformationally constrained analogues of miconazole (1). In vitro and in vivo topical antifungal activity against both dermatophytes and Candida species varied widely, but 13c proved to be significantly superior to both 1 and clotrimazole against a vaginal Candida infection in hamsters, while 13b was significantly more active than 1 against a a topical Trichophyton infection in guinea pigs. None of the compounds were orally active. When the most direct analogue of 1 proved to be among the least active, a molecular modeling study was done using 1, the two active analogues 13b and 13c, and the inactive analogue 13a. All four compounds possessed skeletally similar conformations either at or energetically readily accessible from the global minimum energy conformations. This common conformation of the inactive analogue 13a, however, occupies unique molecular volume space associated with two chlorine atoms, which must also present unique electrostatic properties at the receptor. The conformation-activity relationships discussed may contribute toward deduction of additional structural requirements for pharmacophore optimization and more efficacious antifungal drugs.

Hypertension: cardiovascular implications in a cohort of old old.

OBJECTIVE: To examine the prevalence and cardiovascular implications of hypertension in advanced age. DESIGN: Prospective non-interventional study of a fixed cohort of very elderly subjects. PARTICIPANTS AND SETTING: The subjects were 488 community-dwelling volunteers. Mean age at entry was 79 years (range 75-85). All subjects were ambulatory, non-demented, and free of terminal illness at baseline. Participants were evaluated at the gerontology department of an urban medical school. MAIN OUTCOME MEASURES: Cardiovascular morbid and mortal events that were followed included fatal and non-fatal myocardial infarction, fatal and non-fatal stroke, and death. Prevalence of unrecognized myocardial infarction defined by electrocardiographic changes was also assessed. RESULTS: When hypertension was defined by history, current use of medications, or measured elevations in blood pressure, 78% of the subjects could be considered hypertensive. Univariate analysis showed an increased incidence of strokes in subjects with measured hypertension (P = 0.04). Subjects with elevated blood pressure (untreated) were more likely to develop clinically unrecognized myocardial infarction (P = 0.017). Multivariate survival analysis showed hypertension to be a modest predictor of overall cardiovascular disease (P = 0.067) but not of all-cause mortality. Left ventricular hypertrophy was a predictor of cardiovascular disease (P = 0.013) and all-cause mortality (P = 0.008). Age remained a significant risk factor for these endpoints, even in the very old. Isolated systolic hypertension was analyzed separately and in univariate analysis was a risk factor for stroke but not other cardiovascular morbidity. CONCLUSIONS: Hypertension at advanced age remains a modestly important risk factor in the development of cardiovascular disease.

Prevalence, incidence and prognosis of recognized and unrecognized myocardial infarction in persons aged 75 years or older: The Bronx Aging Study.

The prevalence, incidence and prognosis of recognized and unrecognized Q-wave myocardial infarction (MI) was assessed in an 8-year prospective study of 390 community-based subjects (age 75 to 85 years at entry, mean 79 years). Subjects were studied at baseline and with annual follow-up electrocardiographic (ECG) exams. At baseline, 7.9% had a history of MI without ECG evidence, 6.4% had ECG evidence of Q-wave MI without clinical history, 4.1% had both clinical history and ECG evidence and 81.5% had neither history nor ECG evidence (control subjects). After an average follow-up period of 76.2 months, the total mortality rate was 5.9/100 person-years for subjects with some evidence of MI at baseline versus 3.9 in the control group (p = 0.059). The incidence of cardiovascular disease in subjects with evidence of MI was 8.8/100 person-years versus 4.7 among control subjects (p = 0.002). During the follow-up period, 115 new Q-wave MIs occurred (50 unrecognized, rate 2.4/100; 65 recognized, rate 3.2/100). There was no difference in mortality and morbidity outcome between subjects with recognized and unrecognized MIs. Those with only a history of MI at baseline had a threefold greater risk of a new MI (recognized and unrecognized) than the control group (p = 0.003). Unrecognized Q-wave MI is a common occurrence in the "old old" with subsequent morbidity and mortality prognosis comparable to that of recognized MI. History of MI alone in this age group is also associated with an increased risk of MI, suggesting the need for better diagnostic markers of myocardial ischemia in the old.

Antiulcer agents. 4. Conformational considerations and the antiulcer activity of substituted imidazo[1,2-a]pyridines and related analogues.

Definition of the interrelationship between the conformational characteristics of a series of substituted imidazo[1,2-a]pyridines and their antiulcer activity was investigated by examining the conformational properties of 3-cyano-2-methyl-8-(phenylmethoxy)imidazo[1,2-a]pyridine (1), using a variety of experimental and theoretical methods. The results of these studies was the identification of two distinctly different candidates, designated the "folded" and the "extended" conformation, respectively, to represent the two possible minimum-energy conformations of 1. In order to select the biologically relevant conformer, a group of 3-substituted 2-methylimidazo[1,2-a]pyridines, having either a cis or a trans 2-phenylethenyl substituent at the 8-position were designed as conceptually simple and synthetically accessible semirigid analogues of the respective candidate conformers. Gastric antisecretory activity was found to reside only in the trans isomers (compounds 11, 15, and 17), which mimic the "extended" conformation. This observation led to the construction of 8,9-dihydro-2-methyl-9-phenyl-7H-imidazo[1,2-a]pyrano[2,3-c]pyridi ne-3- acetonitrile (40), a rigid tricyclic analogue that is effectively locked in the "extended" conformation and that exhibited an antiulcer profile comparable to that of prototype 1. These results unequivocally demonstrate that, in accord with expectation for a drug operating at a specific receptor, the conformational characteristics of the molecule have a substantial effect in determining its antiulcer activity. More precisely, it has been demonstrated that it is the "extended" conformation of 1 that represents the "bioactive" form of the drug. These results constitute the basis for a molecular probe that should aid in the investigation of the as yet uncharacterized gastric proton pump enzyme (H+/K+-ATPase), by means of which 1 and its analogues presumably exert their pharmacologic actions.

Antiulcer agents. 2. Gastric antisecretory, cytoprotective, and metabolic properties of substituted imidazo[1,2-a]pyridines and analogues.

The search for a successor to 3-(cyanomethyl)-2-methyl-8-(phenylmethoxy)imidazo[1,2-a]pyridine, Sch 28080 (27), a compound that exhibits gastric antisecretory and cytoprotective properties and has undergone clinical evaluation as an antiulcer agent, has culminated in the identification of four related compounds that exhibit pharmacologic profiles similar to that of 27. In three of these potential successors an amino group functions as a surrogate for the 3-cyanomethyl substituent of the prototype. The present work concerns, in addition to an evaluation of the structure-activity relationships of a series of analogues of 27, preliminary studies of the pharmacodynamics and metabolism of 27, performed with the aid of cyano carbon labeled versions of the drug (13C labeled; 28; 14C labeled, 29). These studies have shown that 27 is well-absorbed and extensively metabolized and that the major metabolite of 27 is the thiocyanate anion. A similar study performed on 3-amino-2-methyl-8-(phenylmethoxy)imidazo[1,2-a]pyridine, labeled at the 3-position with carbon-13 (41) or carbon-14 (42), revealed that this compound, which has an antisecretory/cytoprotective profile comparable to that of 27, is also metabolized to thiocyanate anion, although this must occur via a different mechanism. The chemistry section includes a discussion of the potential sites of protonation of the pharmacologically similar 3-amino analogue 40 and the structurally related imidazo[1,2-a]pyrazine 67. Predictions based on charge density and protonation product stabilities are presented. That N1 is the site of protonation in these analogues has been definitively demonstrated by X-ray crystal structure analysis, which also unequivocally established the assigned imidazo[1,2-a]pyrazine ring structure.

Antiulcer agents. 1. Gastric antisecretory and cytoprotective properties of substituted imidazo[1,2-a]pyridines.

A novel class of antiulcer agents, the substituted imidazo[1,2-a]pyridines, is described. The present compounds are not histamine (H2) receptor antagonists nor are they prostaglandin analogues, yet they exhibit both gastric antisecretory and cytoprotective properties. The mechanism of gastric antisecretory activity may involve inhibition of the H+/K+-ATPase enzyme. Structure-activity studies led to the identification of 3-(cyanomethyl)-2-methyl-8-(phenylmethoxy)imidazo[1,2-a]pyridine, SCH 28080 (27), which was selected for further development and clinical evaluation.

Synthesis of some 5-phenylhexahydroazepino[4,5-b]indoles as potential neuroleptic agents.

5-Phenyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (3a) and five derivatives have been prepared and screened for neuroleptic activity. None of the compounds antagonized methamphetamine aggregate toxicity in mice. A number of compounds, including 3a and its 3-methyl derivative 3d, showed activity in the antidepressant screens.

Selection of succinic dehydrogenase mutants of Neurospora crassa.

A method is described which permits the selection of mutants of Neurospora crassa that are deficient in succinic dehydrogenase activity. The method relies on the observation that succinic dehydrogenase-deficient strains fail to reduce the dye nitrotetrazolium blue when overlaid with the dye in the presence of succinate and phenazine methosulfate. Wild-type colonies reduced the dye and turned blue, whereas mutant colonies remained colorless. In this communication we present studies of a mutant, SDH-1, isolated by this method. The mutant had 18% of the succinic dehydrogenase activity of the parent strain used in the mutation experiments as determined from the ratio of Vmax activities obtained from Lineweaver-Burk plots. The SDH-1 mutant segregated in a Mendelian manner when back-crossed to its parent strain. Succinate oxidase activity in SDH-1 was low and was markedly inhibited by adenosine 5'-diphosphate. The succinate oxidase activity of the parent strain was high and was not affected by the presence of adenosine 5'-diphosphate.