From Kratom to mitragynine and its derivatives: physiological and behavioural effects related to use, abuse, and addiction.

http://www.if-pan.krakow.pl/pjp/pdf/2006/6_777.pdf

Cytisine for the Treatment of Nicotine Addiction: From a Molecule to Therapeutic Efficacy

(−)-Cytisine and Derivatives: Synthesis, Reactivity, and Applications

1. In mice cytisine hydrochloride is less toxic intravenously than nicotine hydrogen tartrate, but more toxic by intraperitoneal or oral administration. Compared with cytisine, caulophylline hydrogen iodide is one-fifth to one-tenth as toxic and caulophylline methiodide is less than one-thirtieth as toxic.2. The surprising low oral toxicity of cytisine and nicotine may be ascribed to the method of administration; if the drug is placed directly in the stomach there is no possibility of absorption through buccal mucous membranes.3. The peripheral effects of nicotine, cytisine and caulophylline are similar, though on some preparations those of nicotine last longer. In most tests cytisine is active in doses from a quarter to three-quarters of those of nicotine, caulophylline in doses from 10 to 20 times those of cytisine. Caulophylline methiodide is virtually inactive.4. Cytisine and caulophylline may differ from nicotine in their central effects.5. Cytisine and caulophylline are active as the cations. The pKa of cytisine is 7.92 and that of caulophylline is 7.04; the difference accounts, in part, for the weaker activity of caulophylline. The caulophylline ion is generally one-sixth to one-third as active as the cytisine ion.6. The introduction of the second methyl group to form the quaternary salt does not appear to cause a dramatic change in the conformation of the molecule. Caulophylline methiodide appears to be feebly active because it has feeble affinity.

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1476-5381.1969.tb07977.x

Some studies on cytisine and its methylated derivatives.

Neuronal nicotinic acetylcholine receptors (nAChRs) form a family of ACh-gated cation channels made up of different subtypes They are widely distributed in peripheral and central nervous systems and are involved in complex cerebral processes as learning, memory, nociception, movement, etc The possibility that subtype-selective ligands be used in the treatment of CNS disorders promoted the synthesis of a large number of structural analogues of nicotine and epibatidine, two very potent nAChR agonists Pursuing our long standing research on the structural modification of quinolizidine alkaloids, we devoted our attention to cytisine, another very potent ligand for many nAChR subtypes Thus a systematic structural modification of cytisine was undertaken in order to obtain compounds of potential therapeutic interest at peripheral as well as central level, with a particular concern for achieving nAChR subtype selective ligands Up to the present more than 80 cytisine derivatives, mainly of N-substitution and a few by modifying the pyridone ring, have been prepared The biological results, which concern so far about an half of the prepared compounds, indicate that the introduction of a nitro group in position 3 of the pyridone nucleus further enhances the high affinity of cytisine, while the introduction of substituents on the basic nitrogen, though reducing in different degrees the affinity, gives rise to compounds with a higher selectivity for central (alpha(4)beta(2)) versus gangliar (alpha(3)-containing) receptor subtype On the other hand, the analgesic, antihypertensive and inotropic activities found in some N-substituted cytisines, represent an attractive starting point for the development of more active compounds

H. Raymond Ing

Papers

420. Cytisine. Part II

129. The alkaloids of Anagyris foetida and their relation to the lupin alkaloids

392. Synthesis of local anœsthetics from cytisine

210. The alkaloids of Mitragyne speciosa. Part I. Mitragynine