PubMed · 4834737
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L L Brown, B A Britt. 1974. Malignant hyperthermia.. https://doi.org/10.1097/00007611-197407000-00013
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2-Aroyl-4-(omega-aminoacyl)- (4) and 4-aroyl-2-(omega-aminoacyl)pyrroles (9) represent a new, structurally novel class of anticonvulsant agents. Compounds of type 4 were prepared by Friedel-Crafts acylation of a 2-aroylpyrrole with an omega-chloroacyl chloride followed by displacement of the chloro group by a primary or secondary amine. Compounds of type 9 were prepared by Friedel-Crafts aroylation of a 2-(omega-chloroacyl)pyrrole followed by displacement by an amine. These compounds were active in the mouse and rat maximal electroshock tests but not in the mouse metrazole test. The lead compound, RWJ-37868, 2-(4-chlorobenzoyl)-4-(1-piperidinyl-acetyl)-1,3,5-trimethylpyrrole++ + (4d), showed potency and therapeutic index comparable to those of phenytoin and carbamazepine and greater than those of sodium valproate. This compound blocked bicuculline induced seizures, did not elevate seizure threshold following iv infusion of metrazole, and blocked influx of Ca2+ ions into cerebellar granule cells induced by K+ or veratridine.
(3 alpha,5 alpha)-3-Hydroxypregnan-20-ones and (3 alpha,5 alpha)-3-hydroxypregnane-11,20-diones bearing a 2 beta-morpholinyl substituent were synthesized, and the utility of these steroids as anesthetic agents was evaluated through determination of their potency and duration of hypnotic activity in mice after intravenous administration. Alkylation of the morpholinyl substituent or chlorination at C-21 afforded the novel amino steroids (2 beta,3 alpha,5 alpha)-3-hydroxy-2-(2,2-dimethyl-4-morpholinyl)-pregnane-11,20-dione (19) and (2 beta,3 alpha,5 alpha)-21-chloro-3-hydroxy-2-(4-morpholinyl)pregnan-20-one (37) that were more potent and advantageously produced shorter sleep times than related compounds which were previously reported. Furthermore, salts of these and other amino steroids generally retained good aqueous solubility. In a radioligand binding assay the compounds inhibited the specific binding of [35S]-tert-butyl bicyclophosphorothionate to rat whole brain membranes, and in an electrophysiological assay they potentiated GABAA receptor-mediated currents recorded from voltage-clamped bovine chromaffin cells. These in vitro results are consistent with the anesthetic activity of the amino steroids being related to their modulatory effects at GABAA receptors.
Although the biological cause of endogenous depression is unknown, one commonly held hypothesis proposes that depression results, in part, from decreased central serotonin (5-HT) neurotransmission. Previous research found that clomipramine (CLI) treatment of neonatal rats produced, in adult rats, a variety of behavioral and physiological dysfunctions resembling those found in human endogenous depression. It was later reported that adult CLI-treated rats exhibited a decreased discharge of 5-HT neurons in the dorsal raphe nucleus (DRN) compared with control rats. This finding, however, was not replicated in subsequent studies that detected differences in DRN receptor function. Several factors were identified that may have contributed to the inability of the latter studies to detect CLI vs. control differences in DRN firing rates and interspike interval histograms (ISIH). Among these were the anesthetic used, the age at which the adult rats were tested, and the location of the recording electrode. The present study controlled these variables by using chloral hydrate anesthesia, testing 'depressed' rats at both 2 and 3 months of age, and verifying electrode location using standard histological techniques. We found that DRN unit firing in 'depressed' rats (0.417 +/- 0.071 spikes/s) was less than half that of 'non-depressed' control rats (i.e. neonatal saline treatment 0.968 +/- 0.12 spikes/s). Additionally, ISIH's indicated that, in addition to the lower firing rate of 5-HT DRN neurons, adult CLI rats had an altered temporal discharge pattern of these neurons. Thus, the ISIH of 5-HT DRN neurons recorded from CLI rats was characterized by a flat distribution suggesting random temporal firing patterns. These results confirm previous findings of decreased DRN firing rates and flat ISIH's in 'depressed' rats and extend previous findings to younger rats of a different strain. The results thereby lend support to the hypothesis of a role for decreased central 5-HT as a substrate for the behavioral deficiencies observed in endogenous depression and suggest that these deficiencies may also result, in part, from a random, rather than orderly, temporal pattern of discharge in these neurons.