Design, synthesis, SAR, and biological evaluation of highly potent benzimidazole-spaced phosphono-alpha-amino acid competitive NMDA antagonists of the AP-6 type.

A series of 2-amino-(phosphonoalkyl)-1H-benzimidazole-2-alkanoic acids was synthesized and evaluated for NMDA receptor affinity using a [3H]CPP binding assay. Functional antagonism of the NMDA receptor complex was evaluated in vitro using a stimulated [3H]TCP binding assay and in vivo by employing an NMDA-induced seizure model. Several compounds of the AP-6 type demonstrated potent and selective NMDA antagonistic activity both in vitro and in vivo. In particular, [R(-)]-2-amino-3-(5-chloro-1-phosphonomethyl-1H-benzoimidazol-2-yl)-propionic acid (1) displayed an IC(50) value of 7.1 nM in the [3H]CPP binding assay and an ED(50) value of 0.13 mg/kg (ip) in the NMDA lethality model. Compound 1, when administered intravenously as a single bolus dose of 3 mg/kg following permanent occlusion of the middle cerebral artery in the rat, reduced the volume of infarcted brain tissue by 45%. These results support a promising therapeutic potential for compound 1 as a neuroprotective agent.

Design and synthesis of [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)-ethyl]phosphonic acid (EAA-090), a potent N-methyl-D-aspartate antagonist, via the use of 3-cyclobutene-1,2-dione as an achiral alpha-amino acid bioisostere.

The diazabicyclic amino acid phosphonate 15, [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid, was identified as a potent NMDA antagonist. It contains the alpha-amino acid bioisostere 3,4-diamino-3-cyclobutene-1,2-dione and an additional ring for conformational rigidity. Compound 15 was as potent as CGS-19755 (5) in the [3H]CPP binding assay, the stimulated [3H]TCP binding assay, and the NMDA-induced lethality model in mice. A single bolus dose of compound 15, administered intravenously following permanent occlusion of middle cerebral artery (MCA) in the rat, reduced the size of infarcted tissue by 57%. Structure-activity relationship (SAR) studies have indicated that the six- and eight-membered ring derivatives had diminished activity and that the two-carbon side chain length was optimum for NMDA receptor affinity. Substitution on the ring was found to be counterproductive in the case of sterically demanding dimethyl groups and of no consequence in the case of an H-bonding hydroxyl group. Replacement of the phosphonic acid group by either a carboxylic acid or a tetrazole group was unproductive. The potent bicyclic NMDA antagonists were synthesized efficiently by virture of their achiral nature and the ease of vinylgous amide formation from squaric acid esters. Compound 15, being a unique NMDA antagonist structural type with a favorable preclinical profile, may offer advantages over existing NMDA antagonists for the treatment of neurological disorders such as stroke and head trauma. Compound 15 is currently under clinical evaluation as a neuroprotective agent for stroke.

Potent quinoxaline-spaced phosphono alpha-amino acids of the AP-6 type as competitive NMDA antagonists: synthesis and biological evaluation.

A series of alpha-amino-3-(phosphonoalkyl)-2-quinoxalinepropanoic acids was synthesized and evaluated for NMDA receptor affinity using a [3H] CPP binding assay. Functional antagonism of the NMDA receptor complex was evaluated in vitro using a stimulated [3H]TCP binding assay and in vivo by employing an NMDA-induced seizure model. Some analogues also were evaluated in the [3H]-glycine binding assay. Several compounds of the AP-6 type show potent and selective NMDA antagonistic activity both in vitro and in vivo. In particular alpha-amino-7-chloro-3-(phosphonomethyl)-2-quinoxalinepropanoic acid (1) displayed an ED50 of 1.1 mg/kg ip in the NMDA lethality model. Noteworthy is alpha-amino-6,7-dichloro-3-(phosphonomethyl)-2-quinoxalinepropanoic++ + acid (3) with a unique dual activity, displaying in the NMDA receptor binding assay an IC50 of 3.4 nM and in the glycine binding assay an IC50 of 0.61 microM.

Bioisosteric replacement of the alpha-amino carboxylic acid functionality in 2-amino-5-phosphonopentanoic acid yields unique 3,4-diamino-3-cyclobutene-1,2-dione containing NMDA antagonists.

In this report, a novel bioisostere of the alpha-amino acid, 3,4-diamino-3-cyclobutene-1,2-dione, has been incorporated into a series of compounds which are NMDA antagonists. These compounds, which are achiral and easily prepared, demonstrated good affinity at the NMDA receptor by their ability to displace [3H]CPP binding in vitro. In particular, the phosphonic acid 24 provided protection against NMDA-induced lethality in mice equivalent to 2-amino-7-phosphonoheptanoic acid (5). This was considered an encouraging result in lieu of the fact that 24, like 5, lacks the conformational rigidity of the more potent NMDA antagonists. In addition, analogs that incorporate the 1,2,4-oxadiazolidine-3,5-dione heterocycle of quisqualic acid and the unsaturation of kainic acid were prepared to explore selectivity at the non-NMDA receptor subtypes.

The effect of two years' training on aerobic power and muscle strength in male and female cadets.

During their first 2 years of training at the U.S. Military Academy, 11 male and 7 female cadets were studied on five occasions. VO2 max (1/min), lean body mass and body weight increased significantly in both groups. Percent body fat was significantly reduced only after the first summer of training and then returned to initial values. VO2 max (ml/kg.min) did not change in males during the study. However, females increased significantly after the initial 6 weeks of training (44.2 to 48.8 ml/kg.min). They remained at this level through the second summer of training. However, by the end of their second academic year, females' values dropped to 45.9 ml/kg.min. Maximal isometric strength measured 30-40% higher in males than in females. During the last year of training, arm and shoulder strength increased 10.2% in males, but was unchanged in females. Our results suggest that even extended military training did not enable females to significantly narrow the difference with male cadets in muscle strength and aerobic power.

The influence of U.S. Army Basic Initial Entry Training on the muscular strength of men and women.

The influence of U.S. Army Basic Initial Entry Training on the maximum voluntary isometric strength (MVIS) and anthropometric parameters of men and women was investigated. Significant increases in weight and lean body mass (LBM) and decreases in percent body fat were found for both sexes during training. Significant increases in the MVIS of the upper torso (UT), leg extensors (LE), and trunk extensors (TE) were also found for both sexes. Females and males improved about the same amount on the LE (12.4% and 9.7%, respectively) but females improved significantly more than males on the UT (9.3% and 4.2%, respectively) and TE (15.9% and 8.1%, respectively). The greater gains in the females were presumably due to their lower initial strength levels and the consequently greater relative training stimulus. When strength was expressed relative to LBM, both sexes were able to exert similar amounts of strength on the LE and TE, suggesting that differences in strength between the sexes may primarily be a function of muscle mass.

Physiological effects of a military training program on male and female cadets.

Tested at the beginning and the end of the 6-week training program which all incoming cadets (plebes) undergo upon entering the U.S. Military Academy were 29 males and 26 females (17-21 years old). The aerobic training consisted of running for 30 min 5-6 d/week at varied speeds depending upon performance in an initial 1.5-mile run test. Females responded to training with a significant increase (p is less than 0.001) in VO2 max from 46.0 +/- 1.0 to 49.7 +/- 0.8 ml/kg.min (7.9%). Males did not increase their initial VO2 max (59.4 +/- 1.1 ml/kg.min) significantly. Both groups significantly reduced HRmax and percent body fat. Their initial VO2 max values and activity history accounted for the lack of a significant increase in this highly-fit population of males. Blood lactates were significantly decreased (p is less than 0.05) at the same two submaximal workloads after training. The initial difference in aerobic power between males and females was reduced from 22% to 18%.

Recommendations for the screening of military personnel over 35 years of age for physical training programs.

Persons over 35 years old have an increased prevalence of risk factors. Careful medical examinations, even in a fit military population, are needed before initiating intensive physical training regimens. Risk factor profiling, which synthesizes major risk factors into a composite score, is a beneficial procedure by which to evaluate individuals. Training programs should be based on several considerations: (1) the individual's age and physical condition; (2) his body composition; (3) his risk factor profile; (4) his preference and physical ability for activity; and (5) the available facilities and climatic conditions. Exercise should enhance work capacity and serve as a preventive measure for coronary heart disease. The most efficient types of exercise to meet these ends are activities that involve the large muscles in continuous activity for 20 to 30 min daily, including warm-up and cool-down periods.

Psychological states and aerobic fitness of male and female recruits before and after basic training.

Psychological states and aerobic fitness were measured using a battery of psychological tests and a bicycle ergometer work test. A group of approximately two hundred male and female subjects were tested at the beginning of a six week basic training cycle and another group of two hundred were tested at the completion of basic training. A difference in mood, anxiety, self confidence and physical fitness was evident in the groups of male recruits, but not in the female recruits after training. A significant difference existed between males and females in terms of physical work capacity. These differences in work capacity and psychological responses should be considered in the assignment and selection of personnel for high work intensity military occupations.

Exercise Tolerance, Coronary Risk Factors, and Aerobic Capacity of Older Military Personnel.

Compared with the nonmilitary population, military men had less body fat and higher aerobic capacities, but similar blood pressure and stress tests. Both groups need this type of screening before fitness programs.