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Background  The 5,8-disubstituted indolizidines constitute the largest class of poison-frog alkaloids. Some alkaloids have been shown to act as noncompetitive blockers at nicotinic acetylcholine receptors but the proposed structures and the biological activities of most of the 5,8-disubstituted indolizidines have not been determined because of limited supplies of the natural products. We have therefore conducted experiments to confirm proposed structures and determine biological activities using synthetic compounds. Recently, we reported that one of this class of alkaloids, (-)- 235B' , acts as a noncompetitive antagonist for α4β2 nicotinic receptors, and its sensitivity is comparable to that of the classical competitive antagonist for this receptor, dihydro-β-erythroidine.    Results  The enantioselective syntheses of (-)- 209B , (-)- 231C , (-)- 233D , (-)- 235B" , (-)- 221I , and what proved to be an epimer of natural  193E , starting from common chiral lactams have been achieved. When we performed electrophysiological recordings to examine the effects of the synthetic alkaloids on two major subtypes of nicotinic receptors (α4β2 and α7) expressed in  Xenopus laevis  oocytes, (-)- 231C  effectively blocked α4β2 receptor responses (IC 50  value, 1.5 μM) with a 7.0-fold higher potency than for blockade of α7 receptor responses. In contrast, synthetic (-)- 221I  and (-)-epi- 193E  were more potent in blocking α7 receptor responses (IC 50  value, 4.4 μM and 9.1 μM, respectively) than α4β2 receptor responses (5.3-fold and 2.0-fold, respectively).    Conclusion  We achieved the total synthesis of (-)- 209B , (-)- 231C , (-)- 233D , (-)- 235B" , (-)- 221I , and an epimer of  193E  starting from common chiral lactams, and the absolute stereochemistry of natural (-)- 233D  was determined. Furthermore, the relative stereochemistry of (-)- 231C  and (-)- 221I  was also determined. The present asymmetric synthesis of the proposed structure for  193E  revealed that the C-8 configuration of natural  193E  should be revised. The selectivity for α4β2 and α7 nicotinic receptors differed markedly for the 5,8-disubstituted indolizidines tested, and thus it appears that the nature of the side chains in these indolizidines is crucial with regard to subtype-selectivity.

beilstein journal of organic chemistry

Flexible synthesis of poison-frog alkaloids of the 5,8-disubstituted indolizidine-class. II: Synthesis of (-)-209B, (-)-231C, (-)-233D, (-)-235B", (-)-221I, and an epimer of 193E and pharmacological effects at neuronal nicotinic acetylcholine receptors