Cytisine structure

Kirch et al. (1995) examined individual plants collected in Corsica, Elba, Sardinia, Liguria, and Provence for alkaloids and observed four groups, one characterized by sparteine [119] (see Fig. 2.34 for structures 119-124), one characterized by lupanine-based alkaloids [120 and 121], one that had a very low level of alkaloid production, and one that lacked sparteine and lupanine-based compounds, but did accumulate other alkaloids such as anagyrine [122], ammodendrine [123], and compounds based on cytisine [124], their outlier group. The distribution of these four chemotypes is presented in Table 2.10. 

Cytisine is a tricyclic quinolizidine alkaloid that binds with high affinity and specificity to nicotinic acetylcholine receptors. In principle, this compound can exist in several conformations, but semi-empirical calculations at the AM 1 and PM3 levels have shown that stmctures 19 and 20 are more stable than other possible conformers by more than 50 kcalmol-1. Both structures differ by 3.7 kcalmol 1 at the AMI level and 2.0 kcalmol 1 at the PM3 level, although this difference is much smaller when ab initio calculations are employed <2001PJC1483>. This conclusion is in agreement with infrared (IR) studies and with H NMR data obtained in CDCI3 solution, which are compatible with an exo-endo equilibrium < 1987JP21159>, although in the solid state cytisine has an exo NH proton (stmcture 19) (see Section 12.01.3.4.2). 

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... 

X-Ray analysis of the cytisine alkaloid dehydroalbine did not confirm the structural formula determined earlier, and the compound was renamed de-... 

Nakai 124-126). UV and IR spectra of 78 and 81-83 are characteristic of lupinine alkaloids of the cytisine series containing an a-pyridine ring. MS fragmentation patterns are similar to those of cytisine alkaloids. The structures of these alkaloids were confirmed by synthesis from cytisine by reaction with HCOOH (81), (CHjCO) (78), C2H5Br (82), or CH2=CH—COCH3 (83). 

The structure of leontidine (126), based on mass spectral evidence, was confirmed by its preparation from cytisine (99). 

Figure 7.10 Structures of the quinolizidine alkaloids, lupinine (21), lupanine (22), cytisine (23) and multiflorine (24) and of a dipiperidine alkaloid of the ammodendrine type (25).

The most common group of alkaloids possessing a quinolizidine nucleus is that of the lupine alkaloids which can simply be classified as bicyclic (lupinine/epilupinine type), tricyclic (cytisine type) or tetracyclic, (sparteine/lupanine or matrine type). Fig. (23). This grouping is made according to structure complexity and without considering biosynthesis, as the detailed biosynthetic pathways are still not completely understood. 

Eurther, a compound collection based on the scaffold of the natural product Euranodictin (Eigure 9.12D) revealed a previously uncharacterized inhibitor class for the protein tyrosine phosphatases PTPIB and Shp-2." A compound collection which embodies the underlying scaffold structure of alkaloid cytisine and related natural products (Figure 9.12E) revealed the first inhibitor class of the vascular endothelial protein tyrosine phosphatase (VEPTP) at a hit rate of 1.57% as well as a completely new class of inhibitors for protein tyrosine phosphatase-IB and the phosphatase Shp-2. These two enzymes are targets for the treatment of the metabolic syndrome and diabetes as well as cancer respectively. In these cases the hit rates were ca. 0.3 to 0.4%. The screens revealed selective inhibitors for the proteins." ... 

Barlow, R.B., Johnson, O., 1989. Relations between structure and nicotine-like activity X-ray crystal structure analysis of (- )-cytisine and (- )-lobeline hydrochloride and a comparison with ( - )-nicotine and other nicotine-like compounds. Br. J. Pharmacol. 98, 799-808. 

Table 6. [3H]Cytisine Binding Affinities (nM) for Pyridyl Ether Compounds of General Structure (Azacycle-CH20-Het) ... 

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... 

The structure of the alkaloids will be considered in the above order of increasing complexity. Related and isomeric alkaloids will be discussed within these five main groups lupinine, cytisine, sparteine, lupanine, and anagyrine. 

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