Antagonists other compounds

Spironolactone is the most clinically usehil steroidal aldosterone antagonist, and unlike GR antagonists, this compound is utilized much more frequendy than aldosterone agonists. Interfering with reabsorption and secretion in the late distal segment, this compound is predominantiy used with other diuretics. Canrenone, an olefinic metaboHte of spironolactone, and potassium canrenoate, in which the C-17 lactone has been hydrolyzed open, are also potent mineralocorticoid antagonists. 

Rimonabant (382) was also included in a clinical study to assess the safety and efficacy of four novel compounds for the treatment of schizophrenia and psychoaffective disorder [378]. The other compounds included in the trial were a neurokinin NK3 antagonist, a serotonin 2A/2C antagonist and a neurotensin NTSl antagonist. Halopeiidol and placebo groups were used as controls in the study. Sixty-nine patients received (382) (20 mg once per day), which failed to demonstrate efficacy in this trial. The reasons for the lack of efficacy may be due to inadequate dosing or an indication that CBi antagonism is not appropriate in the treatment of this condition. 

In general, ketones, alcohols and ethers of formula (3) showed comparable protection against cisplatin-induced emesis in the dog and ferret with that of metoclopramide. Erythro (cis) alcohols (3c, 3g, 3i) were found to be more potent than the corresponding threo-(trans) isomers (3d, 3h, 3j). Optical isomer (.R) (3e) was found to be somewhat more potent than its (S )-enantiomer (3f) as an antagonist of cisplatin-induced emesis in the ferret. In the dog, both isomers showed similar activity. A number of heterocyclic analogues were also studied but with the exception of (3k), all were inferior in potency as antiemetic agents compared with other compounds (3) shown in Table 7.1. Lead compound, BMY 25801, batanopride, (3a) is presently under clinical investigation. 

Several papers discuss the effects of oxygen alone or with other compounds on cyanide toxicity. Oxygen alone results in minimal antagonism in mice injected with potassium cyanide and only slightly enhances the antagonistic effects of sodium nitrite (Sheehy and Way 1968). The antidotal effect of sodium thiosulfate alone or in combination with sodium nitrite, was enhanced by oxygen. 

ETA-selective antagonists included a more selective (>25 000-fold) p)rrrolidine carboxylic acid derivatives A-216546 (121). A-216546 was orally available in rat, dog and monkey and blocked endothelin-1-induced presser response in conscious rats. Replacement of the dialkylacetamide side chain in 121 resulted in a complete reversal of receptor selectivity, preferring ETb over ET. Compound 122 (A-308165) demonstrated over 27 000-fold selectivity favouring the ETb receptor. So far one of the endothelin ETA-receptor antagonists bosentan (123) has reached the market for the treatment of pulmonary h)rpertension. Several other compounds have either failed in the clinic or are in various stages of development (e.g. sitaxsentan (124) and 125). ... 

The other compounds which are agonist-antagonist are levallorphan and cyclazocine which are not used ... 

Interestingly, the two halves bind with much less affinity but cause an efflux of rubidium, suggesting that both act as agonists. Furthermore, acting in a similar fashion to lobeline, the effects of the compounds could not be reversed by mecamylamine or other nicotinic antagonists. These compounds also exhibited a similar pharmacological profile to lobeline in... 

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