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Cannabimimetic Indoles, Pyrroles, and Indenes: Structure–Activity Relationships and Receptor Interactions

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The Cannabinoid Receptors

Part of the book series: The Receptors ((REC))

Abstract

A number of years ago it was found that 1-aminoalkyl-3-aroylindoles have affinity for the canabinoid receptor that is expressed in the central nervous system (CB1 receptor). More than 100 of these aminoalkylindoles were prepared and structure–activity relationships (SARs) were developed for these compounds. Subsequently it was found that the aminoalkyl substituent could be replaced by a straight chain alkyl group of four to six carbon atoms without loss of affinity for the CB1 receptor. One of these indoles, 1-propyl-3-(1-naphthoyl)indole was found to have relatively high affinity for the cannabinoid receptor that is expressed in the periphery (CB2 receptor), but with little affinity for the CB1 receptor. In order to explore the SAR for these cannabimimetic 3-(1-naphthoyl)alkylindoles a number of compounds have been synthesized, some of which have very high affinity for the CB1 receptor and others which are highly selective for the CB2 receptor.

On the basis of a suggested pharmacophore for the cannabimimetic indoles, a series of 1-alkyl-3-(1-naphthoyl)pyrroles was prepared, one of which had modest affinity for the CB1 receptor and was active in vivo. Subsequent work led to the development of a series of 1-alkyl-2-aryl-4-(1-naphthoyl)pyrroles, some of which have high affinity for the CB1 and/or CB2 receptor. Two groups have reported the synthesis of cannabimimetic indenes, which serve as rigid models for the CB1 receptor. Through a combination of molecular modeling and studies of mutant receptors a body of evidence has been acquired, which indicates that cannabimimetic indoles, and by extension pyrroles and indenes, interact with the CB1 and CB2 receptors primarily by aromatic stacking.

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Acknowledgments

The work described in this chapter, carried out at Clemson University and included in the review, was supported by grants DA 03590 and DA15340 from the National Institute on Drug Abuse. The author thanks Drs. Billy R. Martin and Jenny L. Wiley of Virginia Commonwealth University for the pharmacological evaluation of the compounds prepared in our laboratory. The author also thanks Dr. Patricia H. Reggio of the University of North Carolina at Greensboro for the molecular modeling studies of the compounds prepared by our group. Special thanks are extended to the graduate students and postdoctorals at Clemson University who carried out the work from our group described in this chapter. These studies could not have been carried out without their contributions.

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  1. H. L. Hunter Chemistry Laboratory, Clemson University, Clemson, SC 29634-0973, USA

    John W. Huffman

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    Patricia H. Reggio

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Huffman, J.W. (2009). Cannabimimetic Indoles, Pyrroles, and Indenes: Structure–Activity Relationships and Receptor Interactions. In: Reggio, P.H. (eds) The Cannabinoid Receptors. The Receptors. Humana Press. https://doi.org/10.1007/978-1-59745-503-9_3

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