NAchR antagonists

An even simpler protocol for performing nucleophilic substitutions (aminations) and Suzuki reactions in one pot was reported by the Organ group for the generation of a 42-member library of styrene-based nicotinic acetylcholine receptor (nAChR) antagonists (Scheme 6.21) [49]. After considerable experimentation, the authors found that simultaneous nucleophilic displacement and Suzuki coupling could be carried out very effectively by charging the microwave process vessel with the palladium catalyst (0.5 mol% palladium-on-charcoal), the boronic acid [R1B(OH)2], the... 

Scheme 6.21 One-pot nucleophilic substitutions and Suzuki cross-coupling reactions for the synthesis of nAChR antagonists.

The extraordinary antinociceptive potency of the unknown compound was determined in a mouse model of acute nociception, the hot plate test. Despite the Straub-tail effect observed earlier, the antinociceptive effect of the compound could not be not antagonized with the p-opioid receptor antagonist naloxone but with the nAChR antagonist mecamylamine, so the unknown compound was deduced to be a potent nicotinic analgesic (Spande et al., 1992 Qian et al., 1993 Badio and Daly, 1994 Sullivan and Bannon, 1996). 

Epibatidine s antinociceptive effect can be antagonized by pretreatment with the centrally active nAChR antagonist mecamylamine, but not with the peripheral antagonist hexamethonium, so the activation of central nAChRs is presumed to be essential for nicotinic analgesics (Sullivan et al., 1994). The high toxicity of epibatidine has been attributed to its lack of selectivity for specific neuronal nAChR subtypes and has precluded its development as a therapeutic agent. 

Symmetrical methoctramine polyamine derivatives (nAChR antagonist)... 

Epibatidine (9) is a nonopioid analgesic and nicotinic acetylcholine receptor (nAChR) antagonist, and its synthesis involved a key Stille cross-coupling reaction between pyridine stannane 117 and iodide 118 with Pd[(o-tolyl)3P]2Cl2 as the catalyst to form 1197 ... 

The observation that the analgesic action, despite the Straub tail phenomenon, cannot be inhibited by the opiate antagonist Naloxone, but by the non-competitive nAChR antagonist mecamylamine, indicates that epibatidine binds not at opiate receptors, but instead at nicotinic acetylcholine receptors. [547, 549, 550]... 

The a-conotoxins of cone snails, twelve to sixteen amino acids in length, are among the smallest known peptidic, nAChR antagonists (Fig. 8.40). [132,133] These bind with remarkable selectivity at the different subtypes of neuronal nicotinic receptors and at those of the neuromuscular endplate. The a-conotoxin Mil (GlyCysCysSerAsnProValCysHisLeuGluHisSerAsnLeuCysNH2 [134]) from Conus magnus, for instance, inhibits the (a3)2(P2)3"teceptor in the low to sub-nanomolar region, with a > 200-fold selectivity over related receptors. 

The effects of nicotine on memory and LTP are prevented by mecamylamine, a nonselective nAChR antagonist, suggesting that most likely nicotine induces its effects on memory and LTP by acting cm nAChRs in the hippcx ampus [6, 51, 53-55]. 

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