Nicotine partial agonists

Cotinine (NIH 10498) LecTec Pyrrolidinyl pyridine (nicotine metabolite) Nicotinic partial agonist... 

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. 

Another barbiturate (phenobarbitone (Luminal)) and a newer drug lamotrigine (Lamictal) are used to treat epilepsy. Trazodone (Molipaxin) is a useful anti-depressant with fewer side-effects than some of the older drugs. The action of varenicline (Champix), used to treat smoking withdrawal, has a straightforward mechanism, being a nicotinic partial agonist. 

Some antagonists combine the ability to block open ion channels with a competitive action at or near the agonist binding site. A well-characterized example is the nicotinic blocker tubocurarine (see Chapter 6). Agonists may also be open channel blockers, thus limiting the maximal response that they can elicit. Such agents (e g., decamethonium) may therefore behave as partial agonists when tested on an intact tissue ... 

Varenicline is a partial agonist that binds selectively to nicotinic acetylcholine receptors with a greater affinity than nicotine, thus producing an attenuated response compared to that of nicotine. Its place in therapy has not been established. 

Alternative pharmacological approaches Clonidine, an o2 adrenergic agonist, has been employed as adjunctive therapy to assist in smoking cessation. However, results have been mixed or the effects small (Gourlay et al. 1994 Hilleman et al. 1993 Franks et al. 1989). Buspirone (BuSpar) is a 5-HTlA partial agonist with anxiolytic effects. It has been tested as a treatment for smoking cessation because anxiety is a prominent feature of nicotine withdrawal (Farid and Abate 1998). To date, results have been mixed and more controlled research is needed. 

Acetyichoiine Lobeline acts as a partial agonist at nicotinic receptors. It displaces nicotine with a low nanomolar affinity in the rat brain (Damaj et al. 1997). Similar to nicotine, it may act as an antagonist through persistent activation and desensitization of the receptor (Briggs and McKenna 1998 Tani et al. 1998). Lobeline shows a greater affinity for the pZ subunit of the nicotinic receptor than jS4 subunits (Parker et al. 1989). 

Jorenby DE, Hays JT, Rigotti NA, Azoulay S, Watsky EJ, Williams KE, et al (2006) Efficacy of varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation a randomized controUed trial. JAMA 296(l) 56-63... 

Studies with Nicotinic Antagonists and Partial Agonists. 312... 

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

Caggiula AR, Donny EC, Chaudhri N, Perkins KA, Evans-Martin EF, Sved AF (2002) Importance of nonpharmacological factors in nicotine self-administration. Physiol Behav 77 683-687 Cahill K, Stead LF, Lancaster T (2007) Nicotine receptor partial agonists for smoking cessation. 

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