Pirenzepine

FIGURE 6.6 Schilcl regression for pirenzepine antagonism of rat tracheal responses to carbachol. (a) Dose-response curves to carbachol in the absence (open circles, n = 20) and presence of pirenzepine 300 nM (filled squares, n = 4), 1 jjM (open diamonds, n=4), 3j.lM (filled inverted triangles, n = 6), and 10j.iM (open triangles, n = 6). Data fit to functions of constant maximum and slope, (b) Schild plot for antagonism shown in panel A. Ordinates Log (DR-1) values. Abscissae logarithms of molar concentrations of pirenzepine. Dotted line shows best line linear plot. Slope = 1.1 + 0.2 95% confidence limits = 0.9 to 1.15. Solid line is the best fit line with linear slope. pKB = 6.92. Redrawn from [5],... 

Subtype-preferring antagonists (examples)3 Pirenzepine Tripitramine Darifenacin PD102807 C... 

C5H12N2 109-01-3) see Azimilide hydrochloride Chlorcyclizine Clozapine Cyclizine Diethylcarbamazine Fleroxacin Hexocyclium metilsulfate Levofloxacin Loprazolam Loxapine Ofloxacin Olanzapine Pefloxacin Perlapine Pipebuzone Pirenzepine Prochlorperazine Rufloxacin hydrochloride Sildenafil Tiotixene... 

C7H4CINO3 610-14-0) see Glafenine Pirenzepine iV-(4-nitrobenzoyl)-L-glutamic acid C12H12N2O7 6758-40-3) see Methotrexate... 

A growing number of other diverse compounds have also been shown to bind to an allosteric site on the muscarinic receptors. Among them are pirenzepine (highly selective for Mi receptor), lidocaine and verapamil (ion channel blockers), tacrine (anticholinesterase compound), batrachotoxin, and strychnine (glycine receptor antagonist) [25,31-35],... 

Roeske WR, Venter JC. The differential loss of [3H]pirenzepine vs [3H] (-)-quinuclidinylbenzilate binding to soluble rat brain muscarinic receptors indicates that pirenzepine binds to an allosteric state of the muscarinic receptor. Biochem Biophys Res Commun 1984 118 950-957. 

EEG slow waves. The differential EEG and ACh responses to dialysis delivery of AF-DX 116 (M2/M4) versus pirenzepine (M1/M4) supports the conclusion that, in B6 mouse, postsynaptic muscarinic receptors of the Ml subtype form one receptor mechanism by which ACh activates the EEG (Douglas et al, 2002a). The data summarized in Fig. 5.11 provide direct measures of G protein activation in basal forebrain and prefrontal cortex by muscarinic cholinergic receptors (DeMarco et al, 2004). The in vitro data of Fig. 5.11A indicate the presence of functional muscarinic receptors in regions of B6 mouse prefrontal cortex where in vivo microdialysis studies (Douglas et al, 2002a, b) revealed modulation of ACh release and EEG by pre- and postsynaptic muscarinic receptors (Figs. 5.9 and 5.10). 

Lauterbach, F., Intestinal permeation of nonquatemary amines a study with telenzepine and pirenzepine in the isolated mucosa of guinea pig jejunum and colon, J. Pharmacol. Exp. Ther. 1987, 243, 1121-1130. 

Bonnet, D., Ilien, B., Galzi, J.-L., Riche, S., Antheaune, C., and Hibert, M. (2006) A rapid and versatile method to label receptor ligands using click chemistry Validation with the muscarinic Ml antagonist pirenzepine. Bioconjugate Chem. 17, 1618-1623. 

The binding properties of the antagonist pirenzepine led to the initial classification of muscarinic receptors 205... 

Both nicotinic and muscarinic receptors are widespread in the CNS. Muscarinic receptors with a high affinity for pirenzepine (PZ), M, receptors, predominate in the hippocampus and cerebral cortex, whereas M2 receptors predominate in the cerebellum and brainstem, and M4 receptors are most abundant in the striatum. Central muscarinic and nicotinic receptors are targets of intense pharmacological interest for their potential roles in regulating abnormal neurological signaling in Alzheimer s disease, Parkinson s disease and certain seizure disorders. Nicotinic receptors are largely localized at prejunctional sites and control the release of neurotransmitters [10,11],... 

There is also evidence for cholinergic involvement in caffeine analgesia (Ghelardini et al. 1997). The muscarinic antagonists atropine and pirenzepine, and the choline uptake inhibitor hemicholinium-3 prevent caffeine analgesia. In contrast, it was unaffected by an opioid antagonist (naloxone) or a tyrosine hydroxylase inhibitor (o-methyl-p-tyrosine). 

To date, five subtypes of these receptors have been cloned. However, initial studies relied on the pharmacological effects of the muscarinic antagonist pirenzepine which was shown to block the effect of several muscarinic agonists. These receptors were termed Mi receptors to distinguish them from those receptors for which pirenzepine had only a low affinity and therefore failed to block the pharmacological response. These were termed M2 receptors. More recently, M3, M4 and M5 receptors have been identified which, like the Mi and M2 receptors occur in the brain. Recent studies have shown that Mi and M3 are located posts)maptically in the brain whereas the M2 and M4 receptors occur pres)maptically where they act as inhibitory autoreceptors that inhibit the release of acetylcholine. The M2 and M4 receptors are coupled to the inhibitory Gi protein which reduces the formation of cyclic adenosine monophosphate (cyclic AMP) within the neuron. By contrast, the Mi, M3 and M5 receptors are coupled to the stimulatory Gs protein which stimulates the intracellular hydrolysis of the phosphoinositide messenger within the neuron (see Figure 2.8). 

Fig. 2.14 Structures of pirenzepine and its more potent, slow offset Ml antimuscarinic analogue telenzepine.

Gastric secretion. Stimulation of gastric acid production by vagal impulses involves an M-cholinoceptor subtype (M -receptor), probably associated with enterochromaffin cells. Pirenzepine (p. 106) displays a preferential affinity for this receptor subtype. Remarkably, the HCl-secreting parietal cells possess only Ma-receptors. Mi-receptors have also been demonstrated in the brain however, these cannot be reached by pirenzepine because its lipophilicity is too low to permit penetration of the blood-brain barrier. Pirenzepine was formerly used in the treatment of gastric and duodenal ulcers (p. 166). 

The cholinoceptor antagonist pi-renzepine, unlike atropine, prefers cho-linoceptors of the Mi type, does not penetrate into the OIS, and thus produces fewer atropine-like side effects (p. 104). The cholinoceptors on parietal cells probably belong to the M3 subtype. Hence, pirenzepine may act by blocking Ml receptors on ECL cells or submucosal neurons. 

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