Academic Staff - Professor Robin Ganellin FRS Emeritus Professor of Medicinal Chemistry

Synthesis Drug Design Structure-Activity Analysis

tel: +44 (0)20 7679 4624 fax: +44 (0)20 7679 7463 internal: 24624 email: c.r.ganellin@ucl.ac.uk

Professor Ganellin is no longer supervising postgraduate students or postdoctoral associates.

Our research is focused on the design of novel biologically active compounds as prototype drugs. In this we are involved in the synthesis of new compounds and in studying relationships between chemical structure and biological activity. We collaborate with biologists from other research groups who carry out the biological testing.

A. Histamine Receptors

Histamine H3 receptors exist in histaminergic neuronal pathways in the brain and periphery and they function to limit histamine synthesis and release and also to modulate the release of other important transmitter amines. We have designed and synthesized potent H3 receptor histamine agonists and antagonists which penetrate the brain, to provide pharmacologists with a better opportunity to study the role of H3 receptors in the central nervous system. We were the first research group to design potent non-imidazole-containing H3 receptor histamine antagonists. One such analogue is now progressing through phase III clinical trials.

B. Potassium Ion Channels

Potassium ions enter animal cells through special selective ion channels and the resulting polarisation has an important influence on the functioning of cells. More than twenty kinds of K + channel have been identified in cell membranes, including those from vascular tissue, nerve cells, intestinal muscle and liver cells.

This is a current area for biological study which is waiting for medicinal chemists to design compounds with selective actions. We are particularly interested in blocking Ca 2+ activated K + channels and have synthesized analogues of compounds such as apamin, cetiedil and dequalinium which served as leads to provide more specifically acting materials. We have prepared some very potent compounds such as UCL 1684 and UCL 1848 in collaboration with the Pharmacology Department who conducted the biological testing.

C. Proteinases

We have designed compounds as the first inhibitors (eg. Butabindide) of the proteinase enzyme TPP II (tripeptidyl peptidase II) which terminates the activity of the neurotransmitter cholecystokinin (CCK-8). Such compounds may be useful in treating obesity. One such compound, UCL 2000, progressed into phase I clinical studies.

D. Transporters

Transport-P has been defined in the past decade as a post-synaptic uptake process for amines in peptidergic neurones of the hypothalamus. It has been proposed as a new approach to designing antidepressant drugs. We have been working to identify the pharmacophore of compounds that are accumulated by this process and to design compounds that would activate this transport system.

Selected Publications

1. N. Pelloux-Léon, A. Fkyerat, A. Piripitsi, W. Tertiuk, W. Schunack, H. Stark, M. Garbarg, X. Ligneau, J.-M. Arrang, J.-C. Schwartz and C. R. Ganellin. Meta-Substituted Aryl(thio)ethers as Potent Partial Agonists (or Antagonists) for the Histamine H3 Receptor Lacking a Nitrogen Atom in the Side Chain. J. Med. Chem. 2004, 47, 3264-3274.
2. C.R. Ganellin, F. Leurquin, A. Piripitsi, J-M. Arrang, M. Garbarg, X. Ligneau, W. Schunack and J-C. Schwartz. Synthesis of Potent Non-imidazole Histamine H3-Receptor Antagonists. Arch. Pharm. Pharm. Med. Chem. 1998, 331, 395-404.
3. J. Campos Rosa, D. Galanakis, C.R. Ganellin, P.M. Dunn and D.H. Jenkinson. Bis-Quinolinium Cyclophanes: 6,10-Diaza-3(1,3),8(1,4)-dibenzena-1,5(1,4)-diquinolinacyclophane (UCL 1684), the First Nanomolar, Non-Peptidic Blocker of the Apamin-Sensitive Ca 2+ -Activated K + Channel. J. Med. Chem. 1998 , 41, 2-5.
4. C. R. Ganellin, P. B. Bishop, R. B. Bambal, S. M.T.Chan, B. Leblond, A. N.J. Moore, L. Zhao, P. Bourgeat, C. Rose, F. Vargas, J.-C. Schwartz. Inhibitors of Tripeptidyl Peptidase II. 3. Derivation of Butabindide by Successive Structure Optimizations Leading to a Potential General Approach to Designing Exopeptidase Inhibitors. J. Med. Chem. 2005, 48, 7333-7342.
5. P.A. Zunszain, C. Federico, M. Sechi, S. Al-Damluji and C.R. Ganellin. Search for the Pharmacophore in Prazosin for Transport-P. Bioorg. Med. Chem. 2005, 13, 3681-3689.
6. C.R. Ganellin and D.J. Triggle. Dictionary of Pharmacological Agents. Chapman and Hall, London-New York, 1997.
7. J. Fischer and C.R. Ganellin, Analogue-Based Drug Discovery. Wiley-VCH, Weinheim, 2006.
   
   

This page last modified 20 October, 2009