A receptor which is capable of producing a biological response in the absence of a bound ligand is said to display "constitutive activity".  The constitutive activity of a receptor may be blocked by an inverse agonist . The anti-obesity drugs rimonabant and taranabant are inverse agonists at the cannabinoid CB1 receptor and though they produced significant weight loss, both were withdrawn owing to a high incidence of depression and anxiety, which are believed to relate to the inhibition of the constitutive activity of the cannabinoid receptor.
In line with a greater understanding of the neuromodulatory role of muscarinic receptors has come a greater focus on the possibility that this receptor family may be effective therapeutic targets in a number of neurological and psychiatric diseases [ 36 ]. Historically this focus has centred on Alzheimer's disease, which is associated with a loss of cholinergic innervation in the cerebral cortex and hippocampus, and is currently treated by enhancing cholinergic transmission via pharmacological inhibition of cholinesterase activity[ 25 ]. Whereas for many years this treatment was thought to have its beneficial affects by stimulation of the M 1 -muscarinic receptor subtype [ 7 ], work on the M 1 -receptor knockout mice has suggested that this receptor subtype may not play such an important role in cognition as previously thought [ 36 ]. Thus, novel anti-Alzheimer drugs that target other muscarinic receptor subtypes, such as the M 2 -, M 4 - and M 5 -muscarinic receptors, are now under more intense consideration. Interestingly, muscarinic receptor modulation of dopaminergic transmission has provided the impetus for the development of muscarinic receptor ligands in the treatment of schizophrenia and Parkinson's disease [ 36 ]. In both cases the focus has been on the M 1 and M 4 -muscarinic receptors, where it has been indicated that agonists to these receptors might be beneficial in schizophrenia and antagonists are likely to be of benefit in Parkinson's disease.
In addition to the therapeutic potential of targeting specific muscarinic receptors in CNS disorders there is still considerable therapeutic potential in the development of muscarinic ligands to the more classical muscarinic-centred disease targets. For example, in the case of chronic obstructive pulmonary disease (COPD) and asthma, that are currently treated with the non-selective muscarinic antagonists ipratropium and tiotropium [ 10 ], there might be significant clinical benefit derived from the development of selective M 2 and M 3 -muscarinic receptor ligands. Similarly, in overactive bladder, improved selectivity of muscarinic receptor ligands would help to reduce unwanted side effects [ 10 ]. Table 2 (adapted from ref [ 36 ]) provides a list of the potential therapeutic applications of compounds that specifically target muscarinic receptor subtypes.
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