The Essence of Agonism

The different categories of smells and aromatic substances can be readily distinguished. Pleasant and fruity odors are generally esters, ketones, and alcohols distinguished by the presence of an oxygen, often double-bonded. Distinctive and less pleasant smells are associated with nitrogen, such as the fishy smells of quaternary amines. The word aromatic conjures up a mental image of ring structures or p-orbitals and a wholesome smell or whiff of a volatile organic compound. The worst smell of all is methyl mercaptan, and sulfurous compounds in general are associated with death and decay, the curate's egg and Hades.

The distinctive chemistries of oxygen-containing -ols and -ones, basic amines, aromatic rings, and sulfurous compounds are responsible for the distinct categories of smells and are the essential features of templates that preferentially react with 7TMRs or GPCRs,6768 for example, piperidine with a basic and aromatic region, or a quaternary nitrogen, or cyclam groups. It is hardly surprising that the receptors responsible for smell discrimination are 7TMRs.

DITHIOL BRIDGE

-H20

ch3c

O HI

CH3NH3'

CLEAVED DITHIOL

chkc;

CH3NH2

S-CH3

Cl-bCk

CHsM-fe

FIGURE 10.10 A mechanism of agonist-induced cleavage of the receptor dithiol bridge. Semi-empirical quantum chemical calculations for the cleavage of cystine by a carboxylic acid and protonated amine. Reproduced with permission from Brandt W, et al, in European Journal of Biochemistry, © 1999 Blackwell Publishing.64

» What are the characteristics of an odo " AROMATIC RING, VOLATILE

* What is a pleasant smell?

* Why do fish smell fishy?

* What is a nasty smell?

-S, SULFUR

» What are the characteristics of an odo " AROMATIC RING, VOLATILE

* What is a pleasant smell?

* Why do fish smell fishy?

* What is a nasty smell?

-S, SULFUR

adrenaline

FIGURE 10.11 Smell molecules are lowest common denominator agonist templates. The major categories of odor molecules have definitive chemistries that are related to the small molecule templates of ligands bioactive at 7TMRs.

adrenaline thioterpineol

FIGURE 10.11 Smell molecules are lowest common denominator agonist templates. The major categories of odor molecules have definitive chemistries that are related to the small molecule templates of ligands bioactive at 7TMRs.

The >1000 genes that encode the olfactory receptors have extremely diverse sequences and each olfactory epithelial cell expresses only one gene. Linda Buck of the Howard Hughes Medical Institute should know, for she developed a single-cell PCR technique to clone many of them. An olfactory chemical will stimulate an array of receptors and cells to different extents, depending upon its structure and their specificity determinants. Many different olfactory stimulants were tested and each was matched to a particular sequence by cloning the individual 7TMR from each of the neurons that fired.69 It was found that only one olfactory 7TMR is expressed by a single neuron, although an array of receptors (and cells) will respond to a single olfactory chemical to different extents. The signals generated in the olfactory sensory neurons are mapped onto the olfactory cortex to produce a combinatorial code for sensing smell.

Some odorants are perceived as having different odors at different concentrations. A striking example is thioterpineol, whose odor is described as 'tropical fruit' at a low concentration, as 'grapefruit' at a higher concentration, and as 'stench' at a still higher concentration. Our studies indicate that an odorant at different concentrations can be recognized by different combinations of olfactory receptors. Thus, a change in the concentration of an odorant can change its receptor code, and this in turn may lead to a change in odor quality.69

Adrenaline is a biogenic amine derived from tyrosine and has a template typical for 7TMR reactivity (Figure 10.11). Certainly, the redox activation of the p-AR51 and the proposed mechanism for disulfide bridge cleavage64 imply that amine, aromatic, and sulfhydryl groups are important for agonist activity. The sulfur aromatic cage that locks retinal into rhodopsin demonstrates the intimacy and synergy of cysteine (with methionine) and tyrosine (with other aromatic rings) in ligand-receptor interactions. The active ingredient of grapefruit juice, 1-p-men-thene-8-thiol, is one of the most powerful odorants known to science and is still detectable at 0.0001 parts per billion. Thioterpineol is probably an effective ligand at many 7TMRs, which raises the interesting and not only philosophical question of what sort of odor do hormones and neurotransmitters have.

The possession of a charge and an aromatic ring is a common feature of agonist activity, but not all ligands have a sulfur or cysteine moiety, unlike the receptors, although the most potent do. Smell molecules are small. The chemicals that smell and the receptors that respond provide the lowest common denominator for agonist activity at 7TMRs.7

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