MECHANISMS OF CHLORPROMAZINE AND CHLORPROMAZINE ISOSTERES ON THE GLYCEMIC RESPONSE IN MICE

Various phenothiazines, tricyclic antidepressants, and antihistaminics were studied to determine their effect on the glycemic response following single dose administration. The phenothiazines induced glycemic responses varying from very pronounced (chlorpromazine, promazine, triflupromazine, trimeprazine, and chlorprothixene) to no effect (pyrathiazine and chlorpromazine sulfoxide). The tricyclic antidepressants and the antihistaminics had little effect on glycemic activity. Compounds inducing a glycemic response in free-fed animals also did so in fasted animals. Structure-activity comparisons with glycemic activity suggest a free sulfur at the 5 position is important in glycemia. Oxygenation of the sulfur, e.g. chlorpromazine sulfoxide, voids chlorpromazine (CPZ) of glycemic activity as does also a bismethylene substitution for the sulfur. Compounds containing the dimethylaminopropyl substitution on the nitrogen at the 10 position are potent inducers of hyperglycemia. Demethylation of the amino group, shortening the side chain, or elongation of the chain by piperazine substitutions for the dimethylamino group reduced glycemic activity. A methyl branch on the side chain appears to be without influence. Substitutions at the 2 position are of lesser importance on glycemia but can be ranked in order of decreasing influence as follows: Cl \u3e H \u3e CF(,3) \u3e OCH(,3). Liver glycogen was found to be important in the CPZ-induced glycemic response. Fasting reduced liver glycogen levels as did the administration of CPZ. Chlorpromazine could further reduce liver glycogen and cause hyperglycemia in fasted animals, but the response was attenuated. Pre-treatment with chlorisondamine blocked the hyperglycemic response of all drugs tested including CPZ and cyproheptadine (CPH). Exogenous epinephrine could still induce hyperglycemia after chlorisondamine pre-treatment. Stress as a result of vehicle injection and repeated orbital sinus punctures will increase blood glucose levels in mice. Chlorisondamine was also capable of blocking this response suggesting the central component of the physical stress-induced glycemic response could be blocked. Dopamine (DA) blockers, CPZ and haloperidol, will induce hyperglycemia, as will the serotonin (5-HT) blockers, CPH and methysergide. Chemical denervation of the adrenals cancels the effects of both the DA and 5-HT blockers on glycemia. This is consistent with a central role in the area of the hypothalamus for both DA and 5-HT in the mediation of blood glucose levels. Oxotremorine, a muscarinic agonist, was able to induce a hyperglycemic response which could be blocked by chlorisondamine. This would suggest that a balance exists between central sympathetic and parasympathetic control over blood glucose similar to the balance with other autonomic functions. These results are consistent with the hypothesis that in the area of the hypothalamus, DA and 5-HT exert an inhibitory role on the cholinergic mediation of the splanchnic innervation of the adrenal medulla. Blocking this inhibitory action causes increased splanchnic activity resulting in epinephrine release from the adrenal medulla and hyperglycemia. The inhibitory effect of DA and 5-HT can also be offset by increasing cholinergic activity. Ganglionic blockade will interrupt this central mediation of blood glucose. In the mouse, the acute CPZ- and CPH-induced hyperglycemia appears to be the result of the centrally mediated block of DA and 5-HT respectively