Histamine H1-agonist potentiation of adenosine-stimulated cyclic AMP accumulation in slices of guinea-pig cerebral cortex: comparison of response and binding parameters.

1 A range of histamine analogues have been examined as potentiators of the adenosine-stimulated accumulation of cyclic adenosine 3',5'-monophosphate (cyclic AMP) in slices of guinea-pig cerebral cortex. Dose-response curves were constructed for the 6 most active compounds and characterized in terms of the IC50, the slope and the maximum response attainable relative to that of histamine. 2 Histamine, 2-thiazolylethylamine and N alpha-methylhistamine produced a maximal or near maximal response. N alpha, N alpha-dimethylhistamine and 2-methylhistamine appear to be partial agonists. 3 The response to all the agonists was practically abolished by mepyramine 1 microM, indicating that the response is mediated largely or wholly via histamine H1-receptors. 4 The relative potencies of the agonists on cyclic AMP accumulation were in general similar to relative potencies in causing contraction of intestinal smooth muscle. The biggest difference was observed with N alpha-methylhistamine. 5 The histamine analogues were also examined as inhibitors of [3H]-mepyramine binding in homogenates of guinea-pig cerebral cortex. The inhibition curves were characterized in terms of IC50, the slope and the maximum percentage inhibition. This last value was compared with the inhibition produced by promethazine 2 microM. 6 For the 6 most potent agonists, the EC50 for cyclic AMP accumulation was compared with the IC50 against [3H]-mepyramine binding, corrected for inhibition of non-receptor binding and for competition with [3H]-mepyramine. With the possible exception of 2-pyridylethylamine, the values did not differ by more than a factor of 3.