ABSTRACT
The aliphatic side chain plays a pivotal role in determining the cannabinergic potency of tricyclic classical cannabinoids. We have synthesized a series of analogues in which the C3 position is substituted either directly or through a one-carbon atom linker with an adamantylamine or with an oxa- or an oxazaadamantane. The oxaadamantane pharmacophore in analogue 16 showed the best binding profile for both receptors.
Subject(s)
Adamantane/analogs & derivatives , Adamantane/chemical synthesis , Cannabinoids/chemical synthesis , Receptor, Cannabinoid, CB1/metabolism , Receptor, Cannabinoid, CB2/metabolism , Adamantane/pharmacology , Animals , Brain/metabolism , Cannabinoids/pharmacology , Cell Line , Humans , In Vitro Techniques , Mice , Models, Molecular , Radioligand Assay , Rats , Structure-Activity RelationshipABSTRACT
The structures of naturally occurring germination stimulants for seeds of the parasitic weeds Striga spp. and Orobanche spp. are described. The bioactiphore in this strigolactone family of stimulants is deduced from a structure-activity relationship and shown to reside in the CD part of the stimulant molecule. A molecular mechanism for the initial stages of seed germination is proposed. The influence of stereochemistry on the stimulant activity is significant. Combining this molecular information leads to a model for the design of synthetic strigolactones. Nijmegen-1 is a typical example of a highly active, newly designed synthetic stimulant. The occurrence of natural stimulants not belonging to the strigolactone family, such as cotylenin and parthenolide, is briefly described. The biosynthesis of natural strigolactones from beta-carotene is analysed in terms of isolated and predicted stimulants. This scheme will be helpful in the search for new strigolactones from root exudates. Protein fishing experiments to isolate and characterise the receptor protein using biotin-labelled GR 24 are described. A receptor protein of 60 kD was identified by this method. Nijmegen-1 has been tested as a suicidal germination agent in field trials on tobacco infested by Orobanche ramosa L. The preliminary results are highly rewarding. Finally, some future challenges in synthesis are described. These include synthesising new natural and synthetic stimulants and establishing the molecular connection between strigolactones as germination stimulants, as the branching factor for arbuscular mycorrhizal fungi and as an inhibitor of shoot branching.
Subject(s)
Germination/drug effects , Lactones/chemistry , Lactones/pharmacology , Orobanche/physiology , Striga/physiology , Lactones/chemical synthesis , Lactones/metabolism , Orobanche/drug effects , Plant Diseases , Plants/metabolism , Striga/drug effectsABSTRACT
[reaction: see text] Metalloenolates derived from alpha,beta-unsaturated alpha-diketones undergo cyclization to alpha-hydroxy cyclopentenones. This is apparently the first reported Nazarov reaction that takes place in the presence of base.
