title: GABA uptake inhibitors. Synthesis and effects on audiogenic seizures of ester prodrugs of nipecotic acid, guvacine and cis-4-hydroxynipecotic acid.
abstract: The pivaloyloxymethyl esters 4 and 5 of the amino acid GABA uptake inhibitors guvacine and nipecotic acid, respectively, were synthesized as potential prodrugs. The half-lives of 4 and 5 for conversion into the parent amino acids were determined under approximate physiological conditions in the presence or absence of human serum. Under the former conditions the half-lives for 4 and 5 were 6.3 hr and 0.8 hr, and, in the absence of serum, 15.5 hr and 1.2 hr, respectively. The compounds 4 and 5 were administered intracerebroventricularly (i.c.v.) or intraperitoneally (i.p.) to DBA/2 mice and their effects on audiogenic seizures determined. In agreement with earlier findings for 5, all phases of the seizure response of the animals were suppressed by compound 4 at doses above 2mmol/kg i.p. At anticonvulsant doses of compound 4, as well as of 5, side effects such as sedation and impairments of motor activities were observed. The ethyl and pivaloyloxymethyl esters 9 and 11 of cis-4-acetoxynipecotic acid, designed as 'double' ester prodrugs of the GABA uptake inhibitor cis-4-OH-nipecotic acid, were synthesized and shown to have very weak anticonvulsant effects. Compounds 9 and 11 did, however, show a broad spectrum of cholinergic side effects. These apparent interactions of 9 and 11 with muscarinic cholinergic receptors have been explained on the basis of the similarity of the structures of 9 and 11 to that of the muscarinic agonist 1-methyl-4-acetoxypiperidine. Furthermore, the structural similarity of 9 and the muscarinic agonist nipecotic acid ethyl ester may, to some extent, underlie the cholinergic profile of 9.
mesh_terms: D000161:Acoustic Stimulation; D000818:Animals; D005260:Female; D018756:GABA Antagonists; D006801:Humans; D007202:Indicators and Reagents; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009539:Nicotinic Acids / Q000097:blood / Q000494:pharmacology*; D009557:Nipecotic Acids / Q000097:blood / Q000494:pharmacology*; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology; D012640:Seizures / Q000503:physiopathology*; D013329:Structure-Activity Relationship; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis*
chemical_list: D018756:GABA Antagonists; D007202:Indicators and Reagents; D009539:Nicotinic Acids; D009557:Nipecotic Acids; D011355:Prodrugs; C015910:guvacine; D005680:gamma-Aminobutyric Acid; C047022:4-hydroxynipecotic acid