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Beilstein J Org Chem
2007 Jan 01;3:30. doi: 10.1186/1860-5397-3-30.
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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.
Kobayashi S
,
Toyooka N
,
Zhou D
,
Tsuneki H
,
Wada T
,
Sasaoka T
,
Sakai H
,
Nemoto H
,
Garraffo HM
,
Spande TF
,
Daly JW
.
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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. 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). 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.
Scheme 1. Syntheses of (-)-209B, (-)-231C, (-)-233D, and (-)-235B".
Scheme 2. Syntheses of (-)-221I and (-)-7 (an epimer of 193E).
Figure 1. Inhibitory effect of (-)-231C on ACh-induced currents in X. laevis oocytes expressing recombinant nicotinic receptors. Currents were recorded in the voltage-clamp mode at -60 mV. Concentrations of ACh used were 1 μM for the α4β2 receptor and 100 μM for the α7 receptor. For test responses, oocytes were preincubated with (-)-231C for 3 min and then exposed to ACh with (-)-231C. A, representative traces showing the ACh-elicited currents in the absence and presence of (-)-231C (3 μM). Horizontal bars indicate the period of perfusion with ACh for 5 s. Vertical scale bars represent 0.5 μA on the α4β2 receptor, and 0.1 μA on the α7 receptor. B, concentration-response curves for (-)-231C on recombinant nicotinic receptors. Current responses to ACh in the presence of (-)-231C in each oocyte were normalized to the ACh responses (control responses) recorded in the same oocytes. Values represent the mean ± S.E.M. for five to six separate experiments.
Figure 2. Inhibitory effect of (-)-221I on ACh-induced currents in X. laevis oocytes expressing recombinant nicotinic receptors. Currents were recorded in the voltage-clamp mode at -60 mV. Concentrations of ACh used were 1 μM for the α4β2 receptor and 100 μM for the α7 receptor. For test responses, oocytes were preincubated with (-)-221I for 3 min and then exposed to ACh with (-)-221I. A, representative traces showing the ACh-elicited currents in the absence and presence of (-)-221I (3 μM). Horizontal bars indicate the period of perfusion with ACh for 5 s. Vertical scale bars represent 0.5 μA on the α4β2 receptor, and 0.1 μA on the α7 receptor. B, concentration-response curves for (-)-221I on recombinant nicotinic receptors. Current responses to ACh in the presence of (-)-221I in each oocyte were normalized to the ACh responses (control responses) recorded in the same oocytes. Values represent the mean ± S.E.M. for five separate experiments.
Figure 3. Inhibitory effect of (-)-epi-193E on ACh-induced currents in X. laevis oocytes expressing recombinant nicotinic receptors. Currents were recorded in the voltage-clamp mode at -60 mV. Concentrations of ACh used were 1 μM for the α4β2 receptor and 100 μM for the α7 receptor. For test responses, oocytes were preincubated with (-)-epi-193E for 3 min and then exposed to ACh with (-)-epi-193E. A, representative traces showing the ACh-elicited currents in the absence and presence of (-)-epi-193E (3 μM). Horizontal bars indicate the period of perfusion with ACh for 5 s. Vertical scale bars represent 0.5 μA on the α4β2 receptor, and 0.1 μA on the α7 receptor. B, concentration-response curves for (-)-epi-193E on recombinant nicotinic receptors. Current responses to ACh in the presence of (-)-epi-193E in each oocyte were normalized to the ACh responses (control responses) recorded in the same oocytes. Values represent the mean ± S.E.M. for five separate experiments.
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