Pharmacophore rings

A five-membered heterocyclic ring packs a relatively large number of polarized bonds into a relatively small molecular space. This provides a convenient framework to which to attach necessary side chains. In some cases, the framework itself is believed to be part of the pharmacophore. 

Hence there are multiple solutions for the final set of 10000 compounds. The final selection can be diversity driven using for example cluster analysis based on multiple fingerprints [63], hole filling strategies by using scaffold/ring analysis (LeadScope [66], SARVision [66]) or pharmacophore analysis [67, 68]. For a review of computational approaches to diversity and similarity-based selections, see the paper of Mason and Hermsmeier [69] and the references therein. 

Compounds with cis double bonds in the side chain were in general found to be more potent and efficacious than their triple-bond congeners, both in in vivo and in in vitro functional assays [98, 106, 107]. QSAR models have been generated for the compounds with unsaturated [108] and l, l -dimethyl [96] side chains to determine more precisely the pharmacophoric requirements of the receptor. It is postulated that for optimum potency, the side chain must be of a suitable length and flexibility to have the ability to loop back so that its terminus is in proximity to the phenolic ring. The widely used, potency enhancing 1 - and 2 -methyl substituents would be expected to increase the tendency of the side chain to adopt a looped back, rather than an extended conformation. 

The term non-classical cannabinoids is applied to a group of bicyclic compounds identified by researchers at Pfizer in the 1980s [129], These compounds lack the pyran ring of the classical cannabinoids and the second phenolic hydroxyl group of the cannabidiols, resulting in a simplified substructure represented by CP 47,497 (192) [130, 131], The non-classical cannabinoids still retain the three main pharmacophoric elements described above for the classical cannabinoids and the SAR in these regions parallels that of the classical cannabinoids [132]. 

Following on from this, and to further exemplify this pharmacophore model, Huffman [182] described a novel hybrid structure that combined the hydroxydibenzopyran ring of THC and the indole moiety of the AAIs into one molecule. It was found that the hybrid molecule (270) had a similar affinity (19 nM) for the CBi receptor in vitro as (67) (41 nM). The compound was also active in vivo in the mouse tetrad model of cannabimimetic activity and had comparable potency to (67) [182]. 

In contrast to this, there are no such structural constraints on a-adrenergic agonists or antagonists. Some of the most active a-sympathomimetic agents in fact contain an imidazoline moiety as part of the pharmacophore. The appropriate ring system can be... 

Substitution of a pyridine ring for a benzene ring often is compatible with retention of biological activity and occasionally this moiety is an essential part of the pharmacophore. Such substitution of =N for CH= is an example of the common medicinal chemical strategy known as bioisosterism. 

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