Various approaches to the synthesis of all four stereoisomers of 2-(1H-imidazol-4-yl)cyclopropylamine (cyclopropylhistamine) are described. The rapid and convenient synthesis and resolution of trans-cyclopropylhistamine is reported. The absolute configuration of its enantiomers was determined by single-crystal X-ray crystallographic analysis. The distinct transcyclopropylhistamine enantiomers were tested for their activity and affinity on the histamine H 3 receptor. (1S,2S)-Cyclopropylhistamine (VUF 5297) acts as an agonist both on the rat cortex (pD 2 ) 7.1; R ) 0.75) and on guinea pig jejunum (pD 2 ) 6.6; R ) 0.75). Its enantiomer, (1R,2R)-cyclopropylhistamine (VUF 5296), is about 1 order of magnitude less active. Both enantiomers show weak activity on H 1 and H 2 receptors. All synthetic attempts to cis-cyclopropylhistamine were unsuccessful. Nevertheless, the results of this study provide an ideal template for molecular modeling studies of histamine H 3 receptor ligands.

A series of a,P-unsaturated carboxylic acids derivatized with camphorsultam 1 as a chiral auxiliary has been stereoselectively cyclopropanated. The selectivity of the reaction produces cyclopropanated products with the 1R.2R absolute configuration as indicated by the optical rotations as well as b y an X-ray structure determination. The temperature dependence of the reaction was studied with three substrates. The highest stereoselectivity was obtained at temperatures above 25 "C. Branching at the a-or P-carbons disfavours complete conversion, and electron-withdrawing substituents at these positions seem to prevent the reaction. The auxiliary was removed b y using titanium(tv) isopropoxide in benzyl alcohol followed b y alkaline hydrolysis of the intermediate ester. The potent 5-HT,, receptor agonist (1 R,2S)-2-(2-hydroxypheny1)-N,N-dipropylcyclopropylamine 13 was synthesized b y this method.Paper 3/0450 1 C

Twelve N,N-dipropyl-substituted derivatives of trans-2-arylcyclopropylamine have been prepared and assayed for their ability to displace [(3)H]-8-OH-DPAT from rat brain 5-HT(1A) receptors. The new derivatives include phenyl (7a), bromo- (7b) and fluorophenyl (7c-e), 2-methoxy-5-fluorophenyl (7h), and 2-hydroxy-5-fluorophenyl (7l) as well as trifluoromethylphenyl (7f) and 2,3-dichlorophenyl (7g) analogues. In the present series of compounds, electron-withdrawing substituents in the phenyl ring appear to decrease the affinity for 5-HT(1A) receptors. In contrast, electron-rich aryl groups, such as 2- or 3-thienyl (7j and 7k, respectively), provide compounds with high affinity. The additional bulk produced by the aromatic moiety in the 2-benzothienyl derivative 7i appears to be detrimental to 5-HT(1A) receptor affinity. The racemic mixtures of the interesting 7j and 7l were resolved into the enantiomers; 7j and 7l exhibited a high enantiomeric 5-HT(1A) receptor affinity ratio (75-fold and 100-fold, respectively). The enantiomers of 7j and 7l were evaluated in vivo by use of biochemical and behavioral tests in rats. Compound (1R,2R)-7j behaved as a partial agonist whereas (1R,2S)-7l appeared as an efficacious 5-HT(1A) receptor agonist, stimulating both autoreceptors and postsynaptic receptors.

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