UB-165 [Nicotinic]

[Smyth]

Type this into google and straight off the bat you get some meaningful hits.

Quite interesting stuff. The thing with nicotinic agonists is that they need to not have binding for neuromuscular junctions. Remember that the nAChRs are the ones that are also the target of nerve gas agents?

The problem is I am not very good at understand this chemical. It is more of a feast for biochemists and alot of the time the actual chemistry is neglected at the expense of going off on a ramble on the various receptor sub-types etc.

 

[BilZ0r]

Look as relatively subtype selective agonsts that are available allready, alpha4-beta2 selective agonists (RJR-2403) are what you're after, though then you'll get a selective addictant.

Some shit I've written on nicotine allready

As always, these things are more complicated than they would seem.

The simple idea that nicotine activates Alpha4-Beta2 receptors and
depolarizes neurons in the VTA and leads to more dopaminergic traffic is
gone, as nicotine desensitizes nAChR over seconds and minutes, but
nicotine mediated dopamine increases last for hours (Pidoplichko et
al., 1997).

Nicotine to VTA slices leads in an increase in sIPSCs and sEPSCs.
Excitatory traffic presumabley from mPFC, inhibitory from interneurons
and striatum. Alpha7 homomers induce a TTX-sensitive increase in
sEPSCs, while Beta2 containing receptors mediate increase in sIPSCs.
(Mansvelder et al., 2002; McGehee et al 1995). After acute nicotine
treatment, there is an increased faluire rate in GABAergic neurons
because of a lose of nature nicotinic drive due to desensitization of
nAChRs. This loss of GABAergic drive, causes disinhibition of
dopaminergic neurons in the VTA and more closely matches the time
course of dopamine release (Mansvelder et al., 2002). It also matches
the subunit selective of nicotines addictive effect, that is to say,
Beta2 containing receptors mediate this change in inhibitory drive and
Beta2 knock out mice neither have the dopamine release caused by
nicotine or the urge to self-administer it. Conversly, Alpha7
selective antagonists do not inhibit nicotine self-administraton
(Grottick et al., 2000).


Grottick AJ, Trube G, Corrigall WA, Huwyler J, Malherbe P, Wyler R,
Higgins GA. Evidence that nicotinic alpha(7) receptors are not
involved in the hyperlocomotor and rewarding effects of nicotine. J
Pharmacol Exp Ther. 2000 Sep;294(3):1112-9.

Mansvelder HD, Keath JR, McGehee DS. Synaptic mechanisms underlie
nicotine-induced excitability of brain reward areas. Neuron. 2002 Mar
14;33(6):905-19.

McGehee DS, Heath MJ, Gelber S, Devay P, Role LW. Science. Nicotine
enhancement of fast excitatory synaptic transmission in CNS by
presynaptic receptors. 1995 Sep 22;269(5231):1692-6.

Picciotto MR, Zoli M, Rimondini R, Lena C, Marubio LM, Pich EM, Fuxe
K, Changeux JP. Acetylcholine receptors containing the beta2 subunit
are involved in the reinforcing properties of nicotine. Nature. 1998
Jan 8;391(6663):173-7.

Pidoplichko VI, DeBiasi M, Williams JT, Dani JA. Nicotine activates
and desensitizes midbrain dopamine neurons. Nature. 1997 Nov
27;390(6658):401-4.

 

[Smyth]

This article is free and relatively good:

http://www.ingentaconnect.com/content/ben/cmc/2001/00000008/00000006/art00005

Although 5 years old, it still contains lots of goodies and is not too heavy.