3-Alkyl-6-chloro-2-pyrones: selective inhibitors of pancreatic cholesterol esterase.

A series of 3-alkyl-6-chloro-2-pyrones with cyclohexane rings tethered to the 3-position was synthesized. The tether ranged from 0 to 4 methylene units. Inhibition of pancreatic cholesterol esterase by this series of pyrones was markedly dependent upon the length of the tether. Dissociation constants as low as 25 nM were observed for 6-chloro-3-(1-ethyl-2-cyclohexyl)-2-pyranone. This class of cholesterol esterase inhibitors functioned as simple competitive inhibitors of substrate binding rather than as suicide substrates or active site inactivators. Trypsin and chymotrypsin were not strongly inhibited by this class of pyrones. Selectivities for cholesterol esterase were greater than 10(3). This is in contrast to 3-aryl-6-chloro-2-pyrones which are nonselective, irreversible inactivators of serine hydrolases. Thus, replacement of the 3-aryl group by an appropriately tethered 3-alkyl ring can produce highly selective inhibitors of cholesterol esterase. A second series of halogen-containing esters was prepared in which cholesterol was esterified with alpha-haloacyl halides. These haloesters were simple substrates of cholesterol esterase with no evidence of irreversible inactivation.

Behavioural effects of adenosine locally applied into ventral hippocampus of adult male rats.

The possible effects of Adenosine (AD), locally applied into the ventral Hippocampus (HPCv) on the expression of general motor activity and some stereotyped behaviours were studied in adult male rats. Locomotion display was recorded in a hole-board equipped with automatic infrared animal activity detectors. Stereotyped behaviours were measured by direct inspection by two observers. Animals were implanted with microinjection cannulae into the HPCv and 72 h later they were injected with saline, or increasing doses of AD. In one experiment rats were microinjected once with saline or Adenosine and general motor activity and exploration were examined. In other experiment, rats were injected into the HPCv twice with saline, the AD-receptors antagonist 1,3-dipropil-methyl-xanthine (DMX) or AD and only stereotyped behaviours were examined. Results of Experiment 1 showed that the 40 nMol dose of AD was significantly effective to inhibit by about 30% several motor activities such as vertical, horizontal and ambulatory behaviours. Results of Experiment 2, showed that grooming was not modified by AD but the dose of 10 nMol increased the time of immobility by about 3 times over controls. DMX was able to block completely the AD effects on immobility. The present results suggest that in the rat AD might modulate the hippocampal-mediated expression of some motor and stereotyped behaviours induced by unknown environments.