ABSTRACT
The structural requirements for stimulation of adenosine A1 agonist binding by 2-amino-3-benzoylthiophenes and related compounds were investigated. Slowing of the dissociation of [3H]N6cyclohexyladenosine binding was used as a specific measure of the allosteric effects of these compounds. The thiophene ring could be replaced with benzene but not with several nitrogen-containing heterocycles. The 2-amino group was required, and at least one hydrogen on the amino group appeared to be necessary for activity. The keto carbonyl was also essential. Alkyl substitution at the 4-position of the thiophene ring increased activity, whereas 5-position substitution appeared to have little effect. Activity was also increased by various substitutions on the phenyl ring, with 3-(trifluoromethyl) showing optimal activity. The phenyl ring could be replaced with cyclohexyl without major loss of activity. 1-Aminofluoren-9-one, a conformationally locked derivative, was active. Based in part in the latter observation, the active conformation is proposed to have an intramolecular hydrogen bond between the amino nitrogen and the carbonyl oxygen. Because the 2-amino-3-benzoylthiophenes showed competitive adenosine antagonism as well as allosteric enhancement, their affinities as competitive inhibitors of [3H]8-cyclopentyl-1,3-dipropylxanthine binding to A1 receptors were also assessed. Structure-activity relationships for competitive antagonism were distinct from those for allosteric enhancement, with ratios between the two activities varying by more than 1000-fold. Of the analogs tested, (2-amino-4,5-dimethyl-3-thienyl)-[3-(trifluoromethyl)phenyl]methanone (PD 81,723) had the most favorable ratio of enhancement to antagonism.
Subject(s)
Receptors, Purinergic/drug effects , Adenosine/analogs & derivatives , Adenosine/antagonists & inhibitors , Adenosine/metabolism , Allosteric Regulation , Animals , Molecular Conformation , Rats , Receptors, Purinergic/metabolism , Structure-Activity RelationshipABSTRACT
The effects of CI-943 (a novel 8-ethyl-7,8-dihydro-1,3,5-trimethyl-1H-imidazo[1,2-c]pyrazolo[3,4- e]pyrimidine compound exhibiting a favorable antipsychotic profile in animal tests) on neurochemical parameters related to biogenic amine neurons have been studied in rat brain. CI-943 (1-40 mg/kg p.o. and 20 mg/kg i.p.) accelerated the turnover of dopamine (DA) in rat brain as demonstrated by the enhancement of levels of the DA metabolites homovanillic acid, 3,4-dihydroxyphenylacetic acid or 3-methoxytyramine and by the enhancement rate of DA synthesis in either striatum or mesolimbic regions. These increases in DA turnover induced by CI-943 are not due to DA receptor blockade as CI-943, unlike known antipsychotics, did not exhibit affinity for DA receptors either in vitro or in vivo and did not affect rat serum basal prolactin levels. Amfonelic acid enhanced the action of haloperidol in increasing striatal homovanillic acid with no effect on that of CI-943 and clozapine, suggesting that CI-943, like clozapine, would be predicted to have a low risk of extrapyramidal side effects as compared to haloperidol. Chronic administration of CI-943 (40 mg/kg i.p.) to rats for 28 days did not affect the affinity or number of striatal DA receptors; in comparison haloperidol (0.5 mg/kg i.p.) caused an increase in number of DA receptors with no change in affinity. Measures of serotonergic function were increased; noradrenergic function was not affected by CI-943, nor did it exhibit affinity for a number of central nervous system receptors in vitro. The molecular mechanism by which CI-943 increases brain DA turnover is not known at this time but appears to be unique in comparison to known antipsychotic agents.
