Alvameline

Alvameline
Clinical data
ATC code
  • None
Identifiers
IUPAC name
  • 3-(2-ethyltetrazol-5-yl)-1-methyl-5,6-dihydro-2H-pyridine
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC9H15N5
Molar mass193.254 g·mol−1
3D model (JSmol)
SMILES
  • n1nn(nc1\C2=C\CCN(C)C2)CC
InChI
  • InChI=1S/C9H15N5/c1-3-14-11-9(10-12-14)8-5-4-6-13(2)7-8/h5H,3-4,6-7H2,1-2H3 checkY
  • Key:RNMOMKCRCIRYCZ-UHFFFAOYSA-N checkY
  (verify)

Alvameline (Lu 25-109) is a M1 receptor agonist and M2/M3 receptor antagonist[1] that was under investigation for the treatment of Alzheimer's disease, but produced poor results in clinical trials[2] and was subsequently discontinued.

Synthesis

Though the exact cause of Alzheimer’s disease is still unclear, evidence points to the utility of increasing acetylcholine (ACh) levels for treating that condition. Most approaches are aimed at devising inhibitors of cholinesterase, the enzyme that destroys ACh. A quite different tack involves developing compounds that have cholinergic activity in their own right. The tetrazole alvameline (8), for example, was developed as a bioisostere of the muscarinic cholinergic compound arecoline. The design devolves on the fact that the proton on a free tetrazole shows a (pKa) comparable to that of a carboxylic acid. Fully substituted tetrazoles as in (), may thus in some ways may be viewed as surrogate esters.

Alvameline synthesis:[3]

Alkylation of nicotinonitrile (accessible from nicotinamide)[4]) (1) with methyl iodide affords the N-methylpyridinium salt (2). Treatment of this intermediate with sodium borohydride reduces it to 3-cyano-N-methyl-1,2,5,6-tetrahydropyridine (3) in which the position of the double bond mimics that in arecoline. Reaction of (3) with ethyl chloroformate results in N-demethylation and consequent formation of the corresponding carbamate. The nitrile group is then transformed to a tetrazole by reaction with sodium azide in the presence of aluminum chloride, one of the standard procedures for building that ring. The surrogate acid is then alkylated with ethyl iodide to afford (6). Treatment with acid then removes the carbamate on the ring nitrogen (7) and the methyl group on the piperidine ring restored using formaldehyde and formic acid under standard Eschweiler–Clarke conditions, yielding the muscarinic agonist alvameline (8).[3]

See also

References

  1. ↑ Sánchez C, Arnt J, Didriksen M, Dragsted N, Moltzen Lenz S, Matz J (June 1998). "In vivo muscarinic cholinergic mediated effects of Lu 25-109, a M1 agonist and M2/M3 antagonist in vitro". Psychopharmacology. 137 (3): 233–40. doi:10.1007/s002130050615. PMID 9683000. S2CID 20740372. Archived from the original on 2000-10-02. Retrieved 2009-12-03.
  2. ↑ Sramek JJ, Forrest M, Mengel H, Jhee SS, Hourani J, Cutler NR (1998). "A bridging study of LU 25-109 in patients with probable Alzheimer's disease". Life Sciences. 62 (3): 195–202. doi:10.1016/S0024-3205(97)01087-4. PMID 9488097.
  3. 1 2 Moltzen, E. K.; Pedersen, H.; Boegesoe, K. P.; Meier, E.; Frederiksen, K.; Sanchez, C.; Lemboel, H. L. (1994). "Bioisosteres of Arecoline: 1,2,3,6-Tetrahydro-5-pyridyl-Substituted and 3-Piperidyl-Substituted Derivatives of Tetrazoles and 1,2,3-Triazoles. Synthesis and Muscarinic Activity". Journal of Medicinal Chemistry. 37 (24): 4085–4099. doi:10.1021/jm00050a006. PMID 7990109.
  4. ↑ "Nicotinonitrile". Organic Syntheses. 33: 52. 1953. doi:10.15227/orgsyn.033.0052.; Collective Volume, vol. 4, p. 706
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