ライフサイエンスコーパス: epibatidine

1 before and after exposure of the columns to epibatidine.

2 AChRs exhibit high-affinity binding for [3H]epibatidine.

3 binding affinity at alpha4beta2-nAChRs than epibatidine.

4 alpha(7) K(i) ratio of 14,000, twice that of epibatidine.

5 ns showed affinities at the nAChR similar to epibatidine.

6 a(4)beta(2) nAChR receptors labeled by [(3)H]epibatidine.

7 hosteric nAChR binding site labeled by [(3)H]epibatidine.

8 ite, as expected from their competition with epibatidine.

9 ceptors show markedly reduced sensitivity to epibatidine.

10 affinity for alpha-bungarotoxin rather than epibatidine.

11 cetylcholine, and the potent nicotine analog epibatidine.

12 M, as measured by competition with (+/-)-[3H]epibatidine.

13 ing sites with differing affinities for [3H]-epibatidine.

14 of nicotinic receptors capable of binding 3H-epibatidine.

15 icotine, acetylcholine, carbamylcholine, and epibatidine.

16 ffects of nicotine as well as the frog toxin epibatidine.

17 l showed low affinity for nAChRs relative to epibatidine.

18 tivity to the nonselective nicotinic agonist epibatidine.

19 otal synthesis of the bioactive alkaloid (-)-epibatidine.

20 ydrogen bond further augments the binding of epibatidine.

21 , but wraps around the agonists lobeline and epibatidine.

22 While NIC (10-30 microM) and epibatidine (0.01-0.1 microM) fully activated human musc

23 rsal root ganglion neurons in culture, (+/-)-epibatidine (1 microM) was able to inhibit the capsaicin

24 e chloro analogue (5a, K(i) = 245 nM) 5a and epibatidine (1) produced dose-dependent analgesia in bot

25 In diabetic animals an agonist (epibatidine, 10(-10) mol/L) or antagonist (hexamethonium

26 Epibatidine (100 nM) induced an increase to an average o

27 ption induced by (+)-epibatidine but not (-)-epibatidine (12 microg/kg, s.c.).

28 ed the same rank orders of potency for (+/-)-epibatidine, 2S-(-)-nicotine, 7R,9S-(-)-cytisine, and 1,

29 The agonists epibatidine, 3-[2(S)-azetidinylmethoxy]pyridine (A-85380

30 In ligand binding studies, [3H]epibatidine ([3H]EB) binds with an affinity of approxima

31 of the sites in the retina measured with [3H]epibatidine ([3H]EB) is approximately 30% higher than wi

32 rdering of potencies in displacing (+/-)-[3H]epibatidine, (-)-[3H]cytisine or (-)-[3H]nicotine bindin

33 ravenous administration matched those of [3H]epibatidine, [3H]norchloroepibatidine, and (+/-)-exo-2-(

34 pical potent nicotinic analgesic agent (+/-)-epibatidine, 5 shows diminished activity in models of pe

35 f 28 microM for acetylcholine, 24 nM for (+)-epibatidine, 6.6 microM cytisine, and 15 microM 1,1-dime

36 and 12 pM, respectively, similar to that of epibatidine (8 pM).

37 Among them is epibatidine, a nicotinic acetylcholine receptor (nAChR)

38 We also determined the structure with bound epibatidine, a potent AChR agonist.

39 The nicotine analogue epibatidine achieves its high potency by taking advantag

40 Application of agonists (nicotine, cytisine, epibatidine) activated a large (100-200 pA/pF) inwardly

41 The overall data show that epibatidine activates muscle receptors by binding with h

42 line receptor binding was measured using [3H]epibatidine after deletion of alpha7, beta2, or beta4 su

43 (-)-nicotine, cytisine, carbachol, and (+/-)-epibatidine all stimulated 86Rb+ efflux, which was block

44 veral of the analogues were equal to that of epibatidine, all of the compounds were weak agonists in

45 Use of [3H]epibatidine allowed detailed characterization of multipl

46 AT-1001 competes with epibatidine, allowing for [(3)H]epibatidine binding to b

47 icotine, like the structurally similar toxin epibatidine, also distinguishes by binding affinity two

48 he alpha 4 beta 2 subtype, placing them with epibatidine among the most potent nAChR ligands describe

49 xpression of nAChRs in monkeys, we used 125I-epibatidine, an agonist at nAChRs containing alpha2 to a

50 These epibatidine analogs have been shown previously to posses

51 The epibatidine analogs produced protracted activation of hi

52 Although not strongly activated by the epibatidine analogs, LS alpha4- and alpha2-containing re

53 receptors were potently desensitized by the epibatidine analogs.

54 ridinyl)-7-azabicyclo[2.2.1]heptane (2i), an epibatidine analogue possessing an electron-releasing am

55 Compound 2i was also the most selective epibatidine analogue with a K(i) of 0.001 nM at alphabet

56 Conformationally constrained epibatidine analogues 20a,b and 23a,b were synthesized u

57 Epibatidine analogues 3- 5, possessing the pyridine ring

58 2'-Fluoro-3-(substituted pyridine)epibatidine analogues 7a-e and 8a-e were synthesized, an

59 With the exception of 1f and 1g, all the epibatidine analogues are full agonists (tail flick test

60 f 2,4-methanoproline) and provides access to epibatidine analogues containing heterocyclic substituen

61 2,3-Disubstituted epibatidine analogues possessing a 2'-amino group combin

62 A series of 2'-substituted-3'-phenyl epibatidine analogues were synthesized and evaluated for

63 A number of 2',3'-disubstituted epibatidine analogues were synthesized and evaluated in

64 d 6 was the key intermediate used to prepare epibatidine analogues where the 2'-chloro group on the p

65 Even though the conformationally restricted epibatidine analogues, 3- 7, and the benzo analogue 8a p

66 Two epibatidine analogues, 6 and 7, which have the 2'-chloro

67 induced by other nicotinic agonists (such as epibatidine, anatoxin, or cytisine) was also powerfully

68 The syntheses of (+/-)-epibatidine and (+/-)-epiboxidine have been accomplished

69 as evaluated by autoradiography using (125)I-epibatidine and (125)I-alphabungarotoxin, respectively.

70 We used [3H]epibatidine and 125I-alpha-bungarotoxin, together with s

71 In addition, (125)I-epibatidine and [(125)I]alpha-bungarotoxin binding in th

72 gic receptors labeled with the ligands [(3)H]epibatidine and [(3)H]AFDX-384 were affected to a much g

73 ha 7, beta 2, and beta 4 mRNA, or in [(125)I]epibatidine and [(3)H]nicotine binding between +/T and +

74 alpha-CtxMII inhibition of striatal 125I-epibatidine and [125I]A-85380 binding with alpha-CtxMII

75 twice daily for 2 weeks decreased both 125I-epibatidine and [125I]iodo-3-[2(S)-azetidinylmethoxy]pyr

76 into the C5 position of the pyridyl ring of epibatidine and A-84543 significantly increased the sele

77 tine were equal to bFGF and were mimicked by epibatidine and blocked by hexamethonium.

78 The present study compares epibatidine and carbamylcholine binding in terms of thei

79 s reveal opposite site selectivities between epibatidine and carbamylcholine; for epibatidine the ran

80 (+)- and (-)-Epibatidine and compounds 1b-d and 1i all possess simila

81 Moreover, unlike epibatidine and cytisine, 5-[(125)I]iodo-A-85380 shows n

82 xpressed human alpha4beta2 nAChRs with [(3)H]epibatidine and identified by Edman degradation the phot

83 PC12 cells were measured by binding with [3H]epibatidine and in functional studies with agonist-stimu

84 ylcholine receptor (nAChR) agonists, such as epibatidine and its molecular derivatives, are potential

85 Occupation by nicotinic agonists, epibatidine and lobeline, and nicotinic antagonists, met

86 binding sites in the brain and indicate that epibatidine and mecamylamine act as 5-HT(3)R antagonists

87 Epibatidine and mecamylamine are ligands used widely in

88 Previous studies that depended on epibatidine and mecamylamine as nAChR-specific ligands,

89 herapeutic agents and also toxicants such as epibatidine and neonicotinoid insecticides with a chloro

90 Epibatidine and related compounds are potent ligands for

91 satisfactory concentration-response data for epibatidine and several other nicotinic agonists.

92 precipitation assays with iodine-125-labeled epibatidine and solubilized human neuroblastoma acetylch

93 rtant for the binding of the larger agonists epibatidine and varenicline, but dispensable for binding

94 of anisotropy were assessed for one agonist (epibatidine) and two antagonists (alpha-bungarotoxin and

95 Arecolone, (+)-epibatidine, and (+/-)-epibatidine were agonists with ac

96 nes, arecolone, eserine (physostigmine), (+)-epibatidine, and (+/-)-epibatidine, with Torpedo nicotin

97 ChRs, which is 26 times greater than that of epibatidine, and a alphabeta/alpha(7) K(i) ratio of 14,0

98 beta4 subunits with 1/1000th the affinity of epibatidine, and exhibits 1/60th and 1/190th the affinit

99 ty for the halpha4beta2 receptor relative to epibatidine, and like epibatidine, many exhibit robust a

100 rs, whereas nicotinoids such as nicotine and epibatidine are cationic and selective for mammalian sys

101 frontal affinity chromatography with [(3)H]-epibatidine as the marker ligand and epibatidine, nicoti

102 sing frontal chromatography with the agonist epibatidine as the marker.

103 (nAChR) subunit in complex with the agonist epibatidine at 3.2 A.

104 exhibits 1/60th and 1/190th the affinity of epibatidine at alpha7 and muscle-type nAChRs, respective

105 eport that the kinetic fingerprints of [(3)H]epibatidine at five heteromeric alphabeta nAChRs and of

106 at equilibrium show that both enantiomers of epibatidine bind to adult and fetal receptors with shall

107 rtments and slowly released, blocking (125)I-epibatidine binding and desensitizing alpha4beta2Rs.

108 the gamma or the delta subunit and measured epibatidine binding and epibatidine-induced single-chann

109 We find that up-regulation of [(3)H]epibatidine binding and function in HEK293 cells stably

110 Receptor numbers were assessed by [(3)H]epibatidine binding and receptor function was measured b

111 centrations of nicotine (1 microM) increased epibatidine binding but functionally deactivated the nic

112 alpha4beta2 receptors, formed high affinity epibatidine binding complexes that are pentameric, traff

113 e nicotinic agonists in displacing (+/-)-[3H]epibatidine binding from spinal cord membranes correlate

114 HCl (A85380) showed a complete block of 125I-epibatidine binding in all regions investigated and did

115 ly, chronic nicotine produced an increase in epibatidine binding in several areas of the brain in bot

116 n control mice, long-term nicotine augmented epibatidine binding in several areas of the brain, inclu

117 gR transgenics, long-term nicotine increased epibatidine binding in some areas but not in the hippoca

118 In addition, we measured epibatidine binding in the brain and transcription statu

119 he caudate-putamen and had no effect on 125I-epibatidine binding in the frontal cortex or thalamus.

120 y significant abnormality was a reduction in epibatidine binding in the granule cell and Purkinje lay

121 earning and a significant increase in [(3)H] epibatidine binding in the hippocampus indicative of rec

122 "cytisine-resistant" sites), resolving [(3)H]epibatidine binding into three different populations, ea

123 [3H]Epibatidine binding is distinctly biphasic.

124 125I-Epibatidine binding sites are expressed throughout the c

125 antly, indicating that most up-regulated [3H]epibatidine binding sites are internal.

126 impermeant ligands indicated that 85% of [3H]epibatidine binding sites are intracellular.

127 We also show that the upregulation of epibatidine binding sites attributable to chronic nicoti

128 (K(i) < 3 nM) competed for a subset of [(3)H]epibatidine binding sites in mouse brain homogenates, bu

129 are previously uncharacterized high affinity epibatidine binding sites in the brain and indicate that

130 ecamylamine either failed to up-regulate [3H]epibatidine binding sites or up-regulated mildly at high

131 This reduction was confined to the [3H]epibatidine binding sites sensitive to inhibition by alp

132 Intracellular [3H]epibatidine binding sites were characterized after elimi

133 All agonists up-regulated [3H]epibatidine binding sites with EC50 values typically 10-

134 inds with high affinity at a subset of [(3)H]epibatidine binding sites with relatively low cytisine a

135 s classifications of the higher-affinity [3H]epibatidine binding sites.

136 w compounds has been carried out using [(3)H]epibatidine binding studies together with functional ass

137 Based on equilibrium and kinetic [(3)H]epibatidine binding studies, we report that the kinetic

138 In these studies [3H]epibatidine binding techniques were used to characterize

139 as a potent competitive inhibitor of (125)I-epibatidine binding to 5-HT(3)Rs.

140 Nicotine was a poor competitor for (125)I-epibatidine binding to 5-HT(3)Rs.

141 phenylbiguanide readily competed with (125)I-epibatidine binding to 5-HT(3)Rs.

142 ompetes with epibatidine, allowing for [(3)H]epibatidine binding to be used for structure-activity st

143 [(125)I]Epibatidine binding to brain membranes showed that the m

144 find that nicotine blocks only 75% of (125)I-epibatidine binding to rat brain membranes, whereas liga

145 rgic agents were used to define specific [3H]epibatidine binding to total (surface and intracellular)

146 nsity of nicotinic receptors measured by [3H]epibatidine binding was 7-fold higher in membranes from

147 mental retardation, although the lower [(3)H]epibatidine binding was apparent.

148 hibition studies showed that the decrease in epibatidine binding was due to loss of alpha-conotoxin M

149 In contrast, [3H]epibatidine binding was not detected from the extracellu

150 High-affinity epibatidine binding was present in the superficial dorsa

151 Kdapp values for [3H]epibatidine binding were 10 pM for alpha2beta2, 87 pM fo

152 evels of alpha3-independent -resistant [125I]epibatidine binding were also seen.

153 ces in nicotinic receptors assessed by [(3)H]epibatidine binding were significant and extensive (65%-

154 trol) exhibited a 55 to 60% decrease in 125I-epibatidine binding, which seemed to be due to a complet

155 of control) had a 40 to 50% decrease in 125I-epibatidine binding.

156 ts, but they fail to be detected using [(3)H]epibatidine binding.

157 ine dihydrochloride (A85380)-resistant [125I]epibatidine-binding nAChR subtypes, respectively.

158 In contrast, most -resistant [125I]epibatidine-binding nAChRs were dependent on alpha3 gene

159 lts show that more than three fourths of the epibatidine-binding receptors at both early and late emb

160 d alpha5 gene products coassemble to produce epibatidine-binding receptors.

161 ever, when receptors are fully desensitized, epibatidine binds in a biphasic manner, with dissociatio

162 of ligand docking simulations suggests that epibatidine binds in a single preferred orientation with

163 Because (i) epibatidine binds more tightly to the alpha gamma-bindin

164 of single-channel currents reveals that (-)-epibatidine binds with 15-fold selectivity to sites of a

165 (125)I-Epibatidine binds with a high affinity to native 5-HT(3)

166 ed activable state, the results suggest that epibatidine binds with unique site selectivity in activa

167 ificantly the antinociception induced by (+)-epibatidine but not (-)-epibatidine (12 microg/kg, s.c.)

168 The effect of (+)-epibatidine but not (-)-epibatidine was significantly in

169 finity for brain nAChR equivalent to that of epibatidine but reduced analgetic activity.

170 line receptor (nAChR) agonists (nicotine and epibatidine), but also the alpha7 nAChR-selective antago

171 seizure sensitivity to the nicotinic agonist epibatidine, but not to the GABA(A) receptor blocker and

172 gand binding density as measured using [(3)H]epibatidine, but reduces the magnitude of up-regulation

173 gy conformer of 4A with (S)-nicotine and (-)-epibatidine can be achieved.

174 In contrast to epibatidine, carbamylcholine shows little site selectivi

175 H-SY5Y cells exhibited the high affinity for epibatidine characteristic of receptors formed from alph

176 muscarinic agonists chemically derived from epibatidine, CMI-936 and CMI-1145, displayed reduced ana

177 Homologous (epibatidine) competition experiments on total (surface a

178 Thus, the addition of the 3'-amino group to epibatidine confers potent antagonist activity to the co

179 tation responses elicited by intrathecal (-)-epibatidine, confirming a role for spinal excitatory ami

180 of alpha4beta2 nAChRs when measured with [3H]epibatidine, cytisine, nicotine, and acetylcholine.

181 HEK293 cells as measured by increased [(3)H]epibatidine density.

182 We determined the activity profiles of three epibatidine derivatives, RTI-36, RTI-76, and RTI-102, wh

183 Repeated administration of (-)-epibatidine desensitized its responses as well as the ca

184 n assays and high affinity binding for [(3)H]epibatidine determined that all mutants retain functiona

185 h the Leu NH, but the potent nicotine analog epibatidine did not.

186 Comparison of [3H]epibatidine displacement in intact M10 cells and membran

187 high-affinity members of the series and (+)-epibatidine display a tight fit superposition of low-ene

188 tivity arises solely from different rates of epibatidine dissociation from the two sites.

189 ivo, ibogaine at 10 mg/kg completely blocked epibatidine-elicited antinociception in mice, a response

190 tane fragment of the potent nicotinic ligand epibatidine eliciting the greatest interaction energy of

191 to other nicotinic agonists, intrathecal (-)-epibatidine elicits dose-dependent increases in pressor,

192 acetylcholine receptors (nAChRs) labeled by epibatidine (Epb) in 11 brain areas.

193 iperzinium iodide (DMPP), cytisine (CYT) and epibatidine (EPI) were investigated on [3H]-norepinephri

194 .001 mg/kg of the nicotinic full agonist (+)-epibatidine ((+)-EPI).

195 ogy of a highly potent 18F-labeled analog of epibatidine, (+/-)-exo-2-(2-[18F]fluoro-5-pyridyl)-7-aza

196 tency for nicotinic agonists was as follows: epibatidine > nicotine = 3-(azetidinylmethoxy)pyridine (

197 over a 7000-fold range, with a rank order of epibatidine >> A85380 > cytisine approximately 1,1-dimet

198 igh-affinity, specific binding of 3H-labeled epibatidine (H-EBDN; macroscopic KD = 10 pM; kon = 0.74/

199 Epibatidine has been shown to be the most potent nicotin

200 tions, the prototypical nicotinic analgesic (epibatidine) has not yet been shown to modulate inhibito

201 In contrast to epibatidine, however, 5-iodo-A-85380 is more selective i

202 To compare the mode of binding of epibatidine in a muscle and a neuronal nAChR, we photola

203 e relate the binding properties of (+/-)-[3H]epibatidine in spinal cord membrane preparations to the

204 Intrathecal (-)-epibatidine, in addition to eliciting an initial and sub

205 te show similar site selectivity, we studied epibatidine-induced activation of mouse fetal and adult

206 K 8644) and calcium blockers on (+)- and (-)-epibatidine-induced antinociception was investigated in

207 ctional assays the lead compound antagonized epibatidine-induced Ca(2+) flux in alpha3beta4-transfect

208 ults established that bupropion (a) inhibits epibatidine-induced Ca(2+) influx in embryonic muscle AC

209 tions for Delta F agreed well with those for epibatidine-induced currents, but were shifted approxima

210 AT-1001 also potently and reversibly blocks epibatidine-induced inward currents in HEK cells transfe

211 subunit and measured epibatidine binding and epibatidine-induced single-channel currents.

212 Epibatidine inhibited serotonin-induced currents mediate

213 y blocking correlated waves of activity with epibatidine into both eyes.

214 Epibatidine is a potent analgetic agent with very high a

215 Thus epibatidine is a potentially valuable probe of acetylcho

216 total synthesis of the natural product, (+)-epibatidine, is also provided.

217 Thus, epibatidine isomers pharmacological effect was different

218 Epibatidine itself was trapped; (125)I-epibatidine slow

219 termined by frontal chromatography for (+/-)-epibatidine (Kd: 0.27 +/- 0.05 nM) > A85380 (Kd: 17.2 +/

220 2 receptor relative to epibatidine, and like epibatidine, many exhibit robust analgesic efficacy in t

221 Thus, (+/-)-epibatidine may inhibit the vanilloid receptor in a mann

222 articular studies of analgesic properties of epibatidine, may need to be reinterpreted with respect t

223 sites in the central nervous system), (125)I-epibatidine (multiple sites), 5-[(125)I]iodo-3-[2(S)-aze

224 6Rb+ efflux assays indicate full efficacy of epibatidine, nicotine, and acetylcholine; partial effica

225 observed binding affinities for the agonists epibatidine, nicotine, and cytisine were consistent with

226 [(3)H]-epibatidine as the marker ligand and epibatidine, nicotine, and methyllycaconitine as the dis

227 Preinjection of blocking doses of unlabeled epibatidine, (-)-nicotine, lobeline and cytisine signifi

228 little effect on the binding affinities for epibatidine of receptors containing also alpha3 and beta

229 as alpha7nAChR agonists such as nicotine and epibatidine offered protection.

230 With measurements of [(1)(2)(5)I]-epibatidine or [(1)(2)(5)I]-bungarotoxin binding to nico

231 MII or inhibition of alpha-CtxMII binding by epibatidine or nicotine.

232 ther in vivo nAChR probes such as 3H-labeled epibatidine or norchloroepibatidine, [3H](-)-nicotine an

233 n a cation-pi interaction with TyrA, whereas epibatidine participates in a cation-pi interaction with

234 affinity-purified alpha4beta2 nAChRs, [(3)H]epibatidine photolabeled alpha4Tyr(195) (equivalent to T

235 a7-, or alpha3-selective agonists (GTS-21 or epibatidine, respectively).

236 sites with lower and higher affinity for [3H]epibatidine, respectively.

237 There was no significant blockade of the epibatidine response at 24 hr after the administration o

238 1-methyl-2-pyrrolidinyl)isoxazole, and (+/-)-epibatidine, resulted in concentration-dependent increas

239 -[3H]cytisine or (-)-[3H]nicotine, (+/-)-[3H]epibatidine reveals two sites; the ratio of high affinit

240 To determine the structural basis for epibatidine selectivity, we introduced mutations into ei

241 at desensitized muscle nicotinic receptors, epibatidine selects by 300-fold between the two agonist

242 the [(3)H]nicotine-, compared with the [(3)H]epibatidine-sensitive nAChR.

243 it is possible that (-)-1 is acting at a non-epibatidine-sensitive receptor subtype to antagonize nic

244 olved three times in poison frogs, decreased epibatidine sensitivity but at a cost of acetylcholine s

245 Epibatidine shares a highly conserved binding site with

246 alphadelta interface forms the low affinity epibatidine site, whereas the alphagamma and alphaepsilo

247 dopaminergic neurons, in contrast to (125)I-epibatidine sites.

248 Epibatidine itself was trapped; (125)I-epibatidine slow release from acidic vesicles was direct

249 between epibatidine and carbamylcholine; for epibatidine the rank order of affinities is alphaepsilon

250 The nicotinic receptor binding the agonist epibatidine (the high affinity receptor subtype, consist

251 n perturbing postnatal retinal activity with epibatidine, the ipsilateral projection fragments and th

252 2 subunits in the M10 cell line by using [3H]epibatidine to measure nAChR in cells in situ and in mem

253 and 4 inhibited the in vitro binding of [3H]epibatidine to nAChRs to a similar degree, with affiniti

254 of less than one in competing with (+/-)-[3H]epibatidine to spinal cord membranes indicating their in

255 agonists-acetylcholine (ACh), nicotine, and epibatidine-to the nicotinic acetylcholine receptor has

256 ious agonists methylcarbamylcholine or (+/-)-epibatidine together with nicotine resulted in less up-r

257 Nicotine exposure increased epibatidine trapping by increasing the numbers of acidic

258 rol conditions and is further impaired after epibatidine treatment.

259 uggested several different binding modes for epibatidine, varenicline, and 5a-g.

260 ptor binding sites measured with (+/-)-[(3)H]epibatidine was increased during the chronic treatment w

261 Epibatidine was more efficacious than ACh at LS receptor

262 The effect of (+)-epibatidine but not (-)-epibatidine was significantly increased by BAY K 8644 pr

263 RTI-36, the analog closest in structure to epibatidine, was the most efficacious of the three compo

264 Arecolone, (+)-epibatidine, and (+/-)-epibatidine were agonists with activation constants of 3

265 fects of the nicotinic agonists nicotine and epibatidine were blocked.

266 Two subtypes of receptors labeled by [3H]epibatidine were found: one that was increased about 4-f

267 ta4 receptor subtype, which binds (+/-)- [3H]epibatidine with a Kd value of 304+/-16 pM and a Bmax va

268 a and mutant delta(S36K+I178F) subunits bind epibatidine with decreased affinity compared to alphadel

269 a and mutant gamma(K34S+F172I) subunits bind epibatidine with increased affinity compared to alphagam

270 (physostigmine), (+)-epibatidine, and (+/-)-epibatidine, with Torpedo nicotinic acetylcholine recept