Roger Nosal

New aza(nor)adamantanes are agonists at the newly identified serotonin 5-HT4 receptor and antagonists at the 5-HT3 receptor

Abstract New aza(nor)adamantanes 1A , 1B , and 1C are described which exhibit properties of both 5-HT4 agonism and 5-HT3 antagonism. In particular, compound 1C [SC-52491], an azanoradamantane, exhibits an EC50 of 51 nM in a functional model of 5-HT4 agonism and potent antagonism, Ki = 1.2 nM, at the 5-HT3 receptor.

Use of atom-transfer radical cyclizations as an efficient entry into a new serotonergic azanoradamantane

Abstract A route to azanoradamantanes is described which makes use of an atom-transfer radical cyclization to afford 3-azabicyclo[3.3.0]octanes 3A and 3B . Subsequent elaboration of exo-allylamine functionality, followed by cyclization of the endo-hydroxymethyl intermediate 9 , affords the new azanoradamantanes 11 and 4 . This new azatricyclic system is useful for producing serotonin 5-HT3 antagonists and 5-HT4 agonists.

Zinc mediated addition of active halides to a glycine cation equivalent: Synthesis of N-Boc-L-propargylglycine

Abstract The reaction of allylic, benzylic and propargylic halides with zinc in the presence of the glycine cation equivalent, methyl N-Boc-2-acetoxyglycine, affords Boc protected amino acid derivatives in high yield. Resolution of methyl N-Boc-propargylglycine with α-chymotrypsin affords N-Boc-L-propargylglycine in 99% e.e..

Synthetic Strategies for the Construction of Enantiomeric Azanoradamantanes

Abstract The amino azanoradamantane hexahydro-2,5b-methano-IH-3aS,3aa,6aa-cyclopenta-[clpyrrole-4a-amine 1 and the corresponding enantiomer ent-1 have been prepared along with benzamide derivatives SC-52491 and SC-52490, respectively, which are of pharmaceutical interest. The key meso-azabicyclo[3.3.0] intermediate 3 was prepared via three separate routes: a [3+2] cycloaddition route, a radical cyclization/ionic cyclization route, and a reductive Pauson-Khand route.

Use of methyl 2-iodo-2-(phenylsulfonyl)-4-pentenoate in atom-transfer radical cyclizations. Entry into annulation products containing carbonyl or exo-methylene functionality

Abstract Methyl 2-iodo-2-(phenylsulfonyl)-4-pentenoate ( 8 )is reacted with N-BOC-allylamine to afford substituted 3-azabicyclo-[3.3.0]octanes ( 10 ) in a process which involves an initial iodine atom-transfer annulation followed by an ionic cyclization. The geminal carbomethoxy and phenylsulfonyl groups are then efficiently converted to either an exocyclic olefin or to a carbonyl group. The latter transformation allows phenylsulfonylacetates to be used as surrogates for acyl radicals in synthesis.

Serotonin 5-HT4 agonist activity of a series of meso-azanoradamantane benzamides

A series of meso-amino(methyl)azanoradamantane benzamides has been prepared and evaluated for 5-HT4 agonism activity in the rat tunica muscularis mucosae (TMM) assay. Compound 8i is the most potent 5-HT4 agonist in the series, with an EC50 of 217 nM.

Design and synthesis of agonists and antagonists of the serotonin 5-HT4 receptor subtype

Publisher Summary This chapter discusses the design and synthesis of agonists and antagonists of the serotonin 5-HT4 receptor subtype. Serotonin is unsurpassed among monoamine neurotransmitters in the number of receptor subtypes reported to-date. Fourteen subtypes of seven major serotonin receptor classes have been identified in the central nervous system, the peripheral nervous system, myeloid/immune cell types, and smooth musculature of mammals. For some time, it has been known that serotonin exerts profound effects in the enteric nervous system (ENS). It has been previously appreciated that 5-HT4 agonism requires a planar orientation of the amide bond and the aromatic ring system. This feature contributes to the potent agonist properties of the ortho-alkoxy benzamides i, wherein intramolecular hydrogen-bonding maintains such a planar conformation.