Chem. Pharm. Bull., 52(3),316-321, March 2004

Regular Articles

Synthesis and Antispasmodic Activity Evaluation of Bis-(Papaverine) Analogues

Jaskiran KAUR,^a Narendra Nath GHOSH,^b and Ramesh CHANDRA^*,b

^a Department of Chemistry, University of Pennsylvania; Philadelphia, Pennsylvania, 19104, U.S.A.: and ^b Dr. B. R. Ambedkar Centre for Biomedical Research, University of Delhi; 110007, Delhi, India. * To whom correspondence should be addressed. e-mail: acbrdu@hotmail.com

A new series of N-substituted bis-(tetrahydropapaverine) ring systems have been synthesised in expectation of better antispasmodic activity in comparison with papaverine. The synthesis of the targeted heterocycles is described along with a discussion of their structure activity relationship. The general synthetic methods of bis-(tetrahydropapaverine) analogues involve tetrahydropapaverine, various piperazines, diisocyanates and diisothiocyanates as starting materials. Pharmacological evaluation involves the in vitro antispasmodic activity on a freshly removed guinea pig ileum using a force displacement transducer amplifier connected to a physiograph. Among the analogues synthesized in the present study, N,N′-bis-[2-carbamoyl-1-(3,4-dimethoxybenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolinyl]piperazine (22), was found to be the most potent muscle relaxant (IC₅₀: 0.31 μM).

Key words papaverine; tetrahydropapaverine; dimer; antispasmodic activity; piperazine; urea