Centrally active antimuscarinic analogs of oxotremorine selectively block physostigmine-induced hypertension, but not peripheral muscarinic vasodepression.

Some tertiary antimuscarinic amines related to oxotremorine were compared with atropine and scopolamine for their ability to block physostigmine-induced hypertension and acetylcholine-induced hypotension in rats. These cardiovascular responses are mediated via muscarinic receptors in the brainstem and on the vasculature, respectively. In urethane-anesthetized rats, physostigmine (77 nmol/kg i.v.) increased mean arterial pressure 40 +/- 5 mm Hg. One hour later, each rat received a single dose of antimuscarinic, then a second bolus of physostigmine 10 min later. Linear regression analysis of antagonist dose-percent inhibition curves showed that all the agents inhibited physostigmine's pressor effect, thus indicating an ability to antagonize brain muscarinic receptors. BM-5 and BoK-1 were estimated to be equipotent with atropine, all having 50% inhibitory doses (ID50) in the 1.5 to 1.8 mumol/kg range. BR-370 and DKJ-21 were 3- and 30-fold less potent, respectively, than atropine in this assay, while scopolamine was the most potent (ID50: 0.039 mumol/kg). In contrast with atropine and scopolamine, the oxotremorine analogs possessed selective central antimuscarinic effects and were completely unable to antagonize the peripheral depressor response. Like atropine, only BM-5 showed significant tachycardiac effects, which suggested that this agent possessed affinity for myocardial muscarinic receptors. These findings support the concept that congeners of oxotremorine behave as centrally selective antimuscarinics at doses which have low peripheral antimuscarinic activity in vivo. This unique pharmacological profile makes them novel probes to study central cholinergic muscarinic mechanisms in cardiovascular regulation.