Muscarinic split receptors

Methoctramine is a well-known muscarinic M2 selective antagonist that in our experiments showed a 15-fold higher affinity for M2 as compared to Mj. The affinity found for the split chimeric M2-trunc/M3-tail receptor was intermediate (Table 1). 

The last two compounds that we tested, SS 62, CH3I and SS 63, CH3I (Fig. 2), have been shown to differentiate clearly between guinea pig atrium and guinea pig ileum when tested in functional experiments, but when they were tested on cell lines stably transfected with muscarinic receptors they completely lost their selectivity (Angeli et al., 1993). The affinity we found for our split chimeric M2-trunc/M3-tail receptor was intermediate between those found for Mj and M3 (Table 1). 

At the moment, we do not know the functional implications that muscarinic receptor interaction may have and further experiments will be necessary to reveal the biological significance of this phenomenon. As GTPyS experiments indicate that the split chimeric M2-trunc/M3-tail receptor binds to G proteins, it is possible that the interaction between M2 and M3 receptors could result in the acquisition of a novel function, similar to what has been shown for the GABAg and the 8 and k opioid receptors. As co-expression of different subtypes of muscarinic receptors in the same cells occurs in several tissues (Weiner et al., 1990 Fukamauchi et al., 1993 Eglen et al., 1994), it is likely that chimeric receptors could be formed in vivo and repre.sent new pharmacological entities. In this respect it is interesting to note that recently, several articles pre-... 

Barbier, P., Colelli, A., Bolognesi, M.L., Minarini, A., Tumiatti, V., Corsini, G.U., Melchiorre, C., Maggio, R., 1998. Antagonist binding profile of the split chimeric muscarinic m2-trunc/m3-tail receptor. Eur. J. Pharmacol. 355, 267-274. 

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