Synthesis, in vitro acetylcholine-storage-blocking activities, and biological properties of derivatives and analogs of trans-2-(4-phenylpiperidino)cyclohexanol (vesamicol)

Abstract

Eighty-four analogues and derivatives of the acetylcholine-storage-blocking drug trans-2-(4-phenylpiperidino)-cyclohexanol (vesamicol) were synthesized, and their potencies were evaluated with the acetylcholine active-transport assay utilizing purified synaptic vesicles from Torpedo electric organ. The parent drug exhibits enantioselectivity, with (-)-vesamicol being 25-fold more potent than (+)-vesamicol. The atomic structure and absolute configuration of (+)-vesamicol were determined by X-ray crystallography. The absolute configuration of (-)-vesamicol is 1R,2R. Structure-activity evidence indicates that (-)-vesamicol does not act as an acetylcholine analogue. Alterations to all three rings can have large effects on potency. Unexpectedly, analogues locking the alcohol and ammonium groups trans-diequatorial or trans-diaxial both exhibit good potency. A potent benzovesamicol family has been discovered that is suitable for facile elaboration of the sort useful in affinity labeling and affinity chromatography applications. A good correlation was found between potencies as assessed by the acetylcholine transport assay and LD50 values in mouse.

The potential ofo-bromo-trans-decalinvesamicol as a new PET ligand for vesicular acetylcholine transporter imaging

“…The bromo substituent of OBDV was replaced by a trimethylstannyl group by the reaction of Pd(PPh 3 ) 4 and hexamethylditin to obtain the corresponding precursor, o-trimethylstannyltrans-decalinvesamicol (OTDV), for the radiosynthesis of [ 77 Br]OBDV, with an yield of 65% (Kozaka et al, 2012). DV was prepared according to Roger's protocol (Rogers et al, 1989). During the purification of [ 77 Br]OBDV with HPLC, no UV peak of OBDV was detected because the concentration of OBDV was less than the detection limit.…”

“…In 1989, Rogers et al reported that trans-decalinvesamicol (DV) revealed high affinity for VAChT among various vesamicol analogues in in vitro and in vivo binding assays ( Fig. 1) (Rogers et al, 1989). On the basis of the observations of DV and (-)-oIV, we synthesized o-bromo-trans-decalinvesamicol (OBDV) and o-iodo-trans-decalinvesamicol (OIDV) (Fig.…”

Imaging of myocardial autonomic innervation in patients with congestive heart failure: Methods and clinical implications

“…Measurement of cardiac norepinephrine spillover to plasma, the difference between release and reuptake, relies on the determination of the norepinephrine concentration difference between the coronary sinus and the arterial system, fractional extraction of tritium-labeled norepinephrine, and coronary sinus blood flow [63,64]. Increased [183,233] p-(lSF)fluorobenzylguanidine [189] 11C-benzovesamicol [191] nC-CGP 12177 [196][197][198] nC-carazolol [199,200] 11C-prazosin [201] 11C-MQNB [202][203][204][205][206] N-(~SF)fluoroethyl-( -)-QNB [207] 11C-PKl1195 [211] 123I-m-iodobenzylguanidine (12~I-MIBG) [69][70][71][72][73][74][75] l~I-iodocyanopindolol (I~I-ICYP) [153][154][155][156] (1~ I)N-methyl-4-iododexetimide [164] cardiac norepinephrine spillover to plasma has been demonstrated using this technique in patients with essential hypertension [65], ventricular arrhythmias [66], myocardial ischemia [67], and congestive heart failure [29,68].…”

“…However, on the outer membrane surface of the ACh storage vesicles, a specific binding site could be characterized using vesamicol, a compound originally designed as an analgetic. High-affinity binding of vesamicol to synaptic vesicles of parasympathetic nerve cells was demonstrated [191]. Tritiated vesamicol and 5-(125I)iodobenzovesamicol were first studied in mice and rats.…”

Synthesis of β-amino alcohols by ring opening of epoxides with amines catalyzed by cyanuric chloride under mild and solvent-free conditions

“…This classical method has a number of limitations, such as the requirement of an excess of inorganic base, longer reaction times, low nucleophilicity in the case of deactivated aromatic amines, and in some cases low boiling points when elevated temperature is necessary (7). Even though some of these drawbacks have been overcome with the use of a variety of catalysts, such as Bi(OTf) 3 (8), InBr 3 (9), Cu(BF 4 ) 4 O (19), there are still many limitations, such as the formation of bisalkylated products, longer reaction times (8,9,11Á18), stoichiometric amounts of catalysts (9,12,14Á16,19), and harsh reaction conditions (15,18). However, some of these reported methods are not applicable for aliphatic amines (8,9,11Á14,17).…”