Cytisine agonist

Cytisine and varenicline are partial agonists with activity at the o4p2 binding site. In tests of nicotine discrimination, pretreatment with cytisine has no... 

Chance WT, Murfin D, Krynock GM, Rosecrans lA (1977) A description of the nicotine stimulus and tests of its generahzation to amphetamine. Psychopharmacology 55 19-26 Chance WT, KaUman MD, Rosecrans lA, Spencer RM (1978) A comparison of nicotine and structurally related compounds as discriminative stimuli. Br 1 Pharmacol 63 609-616 Chandler Cl, Stolerman IP (1997) Discriminative stimulus properties of the nicotinic agonist cytisine. Psychopharmacology 129 257-264... 

Lobeline (3), extracted from Lobelia inflate, interacts with the nicotinic receptor and could also be exploited to influence cholinergic function in AD. Other alkaloids such as sophoramine (4) and cytisine (5), found in members of the Leguminosae, also have nicotinic agonistic properties. ... 

Cytisine (30), from Cytisus scoparius L., has been found to be a selective and specific probe for the nicotinic-type acetylcholine receptor (nAChR) as a partial agonist and has served as the lead compound... 

Cytisine (= Baptitoxine Laburnum anagyrmrks (laburnum) nAChR to evoke D release] nACh-R agonist - 0(432... 

A series of pyridyl ethers, typified by (81) and (82), exhibited high binding affinity at cytisine rat forebrain sites (cytisine is a nicotinic receptor partial agonist), but only moderate affinity at H-epibatidine sites (109, 130). 

The nicotine partial agonist cytisine 201 was prepared by employing a Suzuki reaction (vide supra). The analog ( )-9-methoxycytisine 295 was generated using a Stille reaction [71]. Iodide 292 was coupled with starmane 293 to generate 294, an advanced intermediate in the synthesis of 295. 

The a4p2 nAChR is the predominant heteromeric receptor in the brain, binds nicotine and other nicotinic agonists, e.g. cytisine and epibatidine. As a principal nicotinic AChR is more ubiquitous and is predominant in cortex, striatum, superior colliculus, lateral geniculate nucleus and cerebellum. When activated it facilitates excitatory inputs and is present very early in the developing brain in various brain regions. 

The different combinations of recombinant neuronal nicotinic receptors differ in their sensitivity to agonists. The list of nicotinic agonists is long and consists of both natural compounds such as choline, nicotine, cytisine, lobeline, epibatidine, anabaseine, and synthetic compounds such as tetramethylammo-... 

On the other hand, cytisine is both efficacious and potent as an agonist on heteromers containing the ]84 subunits (i.e., ganglion-type receptors), but is only a partial agonist on j32 heteromers (132, 253, 256). On the latter receptor type, the maximum current to cytisine is no more than 25% of that produced by ACh (the precise value depends on the a subunit, the species from which the clones are derived... 

Figure 12 Nicotinic receptor agonists (-)-cytisine and (-)-mus-carone used (along with two others, not shown) to generate a three-dimensional model of the nicotinic receptor with ensemble distance geometry.

Varenicline, a small (molecular weight 211.27) achiral alkaloid, was identified in 1997 as a potential treatment for smoking cessation. Its selection as our clinical candidate came after years of effort to identify an effective and safe partial agonist selective for the a4(32 nAChR subtype. A majority of the analogs explored in the course of our work were structurally related to the natural product (-)-cytisine and variations thereof.The discovery synthesis shown in Scheme 3.1 is rooted in... 

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