Mouse strain differences in the behavioral effects of corticotropin-releasing factor (CRF) and the CRF antagonist alpha-helical CRF9-41.

The effect of the corticotropin-releasing factor (CRF) antagonist alpha-helical CRF9-41 (alpha H CRF9-41; 25 and 50 micrograms) was examined in four strains of mice (BALB/C, NIH Swiss, CF-1, and CD) in the elevated plus-maze anxiolytic test and found to significantly increase percent open arm activity in only the BALB/C mice. A marginal anxiolytic response was obtained in NIH Swiss, while no effect of the antagonist was noted in CF-1 or CD mice in this test. Diazepam (1-4 mg/kg IP) significantly increased percent open arm activity in all four mouse strains. Thus, all strains were sensitive to the effects of a known anxiolytic in this test. The locomotor-suppressing effect of the agonist CRF was assessed in the four strains of mice. While CRF suppressed locomotor activity in each of the strains, the peptide was more efficacious and more potent in the BALB/C strain than in any of the other three strains. The behavioral differences in responsiveness to CRF and the antagonist alpha H CRF9-41 could not be explained on the basis of differential binding of CRF to forebrain membranes in the four mouse strains. These data suggest that the BALB/C mouse is more sensitive to the behavioral effects of CRF and its antagonist than other strains and may be a useful strain for examining the effects of CRF and/or stress.

1,3,8-trisubstituted xanthines. Effects of substitution pattern upon adenosine receptor A1/A2 affinity.

A series of 11 8-substituted xanthines having three different substitution patterns on the 1- and 3-positions [pattern a (R1 = R3 = CH2CH2CH3), b (R1 = CH2CH2CH3, R3 = CH3), and c (R1 = CH3, R3 = CH2CH2CH3)] was prepared. These compounds were assessed for affinity and selectivity in binding to adenosine A1 and A2 receptors. Compounds with greatest affinity at the A1 receptor had the 1,3-substitution pattern a. With one exception, compounds with pattern a also exhibited the most potent binding at the A2 receptor; however, several compounds with pattern c were equipotent at the A2 receptor with those having pattern a. Additionally, the substituents on the 1- and 3-positions of these 8-substituted xanthines were equally important for determining maximum affinity to the A1 receptor, while the substituent at the 3-position is more important than the substituent at the 1-position for potency at the A2 receptor. As a result of this, it is possible to maximize selectivity for the A1 receptor by choice of the 1- and 3-position substituents. However, the R1/R3 substitution pattern required for maximum A1 selectivity is also dependent upon the substituent in the 8-position in a manner which is not fully understood.