Synthesis and pharmacology of the baclofen homologues 5-amino-4-(4-chlorophenyl)pentanoic acid and the R- and S-enantiomers of 5-amino-3-(4-chlorophenyl)pentanoic acid

(RS)-5-Amino-4-(4-chlorophenyl)pentanoic acid (10) and the R-form (11) and S-form (12) of (RS)-5-amino-3-(4-chlorophenyl)pentanoic acid, which are hom ologues of the 4-aminobutanoic acid(B) (GABA(B)) receptor agonist (RS)-4-am ino-3-(4-chlorophenyl)butanoic acid (baclofen), were synthesized. Compound 10 was synthesized by homologation at the carboxyl end of baclofen using a seven-step reaction sequence. N-Boc-protected (4R,5R)-4-(4-chlorophenyl)-5- hydroxy-2-piperidone (18) was deoxygenated via a modified Barton-McCombie r eaction to give N-Boc-protected (R)-4-(4-chlorophenyl)-2-piperidone (20), w hich was ring opened and deprotected to give 11.HCl. The corresponding S-en antiomer, 12.HCl, was synthesized analogously from the 4S,5S-enantiomer of 18, compound 21. The enantiomeric purities of 11.HCl (ee = 99.8%) and 12.HC l (ee = 99.3%) were determined by chiral HPLC. Compound 10 did not show det ectable affinity for GABA(A) or GABA(B) receptor sites and was inactive as an agonist or an antagonist at GABA(B) receptors in the guinea pig ileum. L ike the enantiomers of baclofen, neither 11 nor 12 showed detectable affini ty for GABA(A) receptor sites, and in agreement with the findings far (S)-b aclofen, 12 did not interact significantly with GABA(B) receptor sites. Com pound 11 (IC50 = 7.4 +/- 0.6 mu M), a homologue of (R)-baclofen (2), was sh own to be some 50 times weaker than 2 (IC50 = 0.14 +/- 0.01 mu M) as an inh ibitor of GABA(B) binding. Accordingly, 11 (EC50 = 150 +/- 23 mu M) was sho wn to be weaker than 2 (EC50 = 11 +/- 1 mu M) as an inhibitor of electrical ly induced contractions of the guinea pig ileum. However, whereas this effe ct of 2 was sensitive to the GABA(B) antagonist, CGP35348 (4), the inhibiti on by 11 was not significantly affected. Furthermore, 12 (EC50 = 310 +/- 16 mu M) was shown to be one-half as potent as 11 in this test system, and th is effect of 12 also was insensitive to 4. The dissimilarities of the pharm acological effects of 2 and compounds 11 and 12 were emphasized by the obse rvation that whereas 2 only inhibits the ileum contraction by 59 +/- 5%, 11 as well as 12 were shown to inhibit this response by approximately 94%. Ne ither 11 nor 12 appeared to affect significantly cholinergic mechanisms in the ileum, and their mechanism(s) of action remain enigmatic.