New pharmacological cores of GPR55 Receptor Antagonists and Agonists.

New pharmacological cores of GPR55 Receptor Antagonists and Agonists.
Rational Drug Design, small molecules.
Independent researcher Yaroslav Grigorievich Zaitsev 0000-0002-0069-2997

Antagonists of GPR55 receptors are promising as anti-inflammatory, immunomodulatory and anticancer agents. The pharmacological design of drugs of this group has a number of characteristic features, such as a close relationship with the structures of cannabinoids of other groups, many strategies for implementing the functions of an agonist and antagonist, difficulties in obtaining high selectivity and special useful combinations of non-selective activity.

Antagonists of GPR55 receptors are perfectly combined with agonists of CB2 receptors, since their pharmacological profiles complement each other, and the structures of endogenous cannabinoids with affinity to GPR55 and CB2 are similar in chemical structure, as are their natural and synthetic agonists. The latter allows implementing the strategy of designing complex agonists and agonist-antagonists to obtain drugs with a wide range of therapeutic effects and synergy.

The main tasks for rational drug design in this work were, development of strategies of antagonists of GPR55 receptors with a unique pharmacological profile, providing pure and simple organic synthesis, absence of toxic and radical inclusions in the structure, timely and safe catabolism, high bioavailability, moderate biostability. And also a range of special physicochemical and pharmacological properties, such as high or low affinity, high or low activity, ability to pass or not pass the blood-brain barrier, ability to linger at the injection sites, internal organs, on the surface of the skin or lungs, ability to be carried by the blood stream upon injection...

All of the above parameters are necessary for the implementation of drugs with different qualities, to achieve high results in the treatment of various pathologies requiring different methods of administration, external or inhalation, subcutaneous or intravenous, central or peripheral.

Also, the development of strategies for complex antagonist-agonists, GPR55 antagonists and CB2 receptor agonists in one structure, as well as GPR55 agonists, which are also being studied for their beneficial properties, requires rather subtle strategies for constructing rational design, which was demonstrated in this work.

The design of such structures is associated with difficulties in obtaining bioavailable structures, which is due to their bulky structure, often due to a large number of heteroatoms with radicals in the form of halogenated aromatic groups. With a decrease in the molecular weight of such structures, biostability often decreases, which sometimes forces one to balance on the edge of possibilities. Such a powerful pharmacological technique as combinatorial heterochemistry cannot always be an answer to any challenge, especially when it comes to mimetics or antagonists of substances that have almost no heteroatoms.

On the other hand, the old school of drug design is often associated with homologues and derivatives of natural cannabinoids, the synthesis of which is difficult and inaccessible, especially in the case of mass synthesis of candidates for the role of a pharmacological drug.

Deadlock and compromises, is there a way out? A useful find in this direction can be a deep rational design including elements of combinatorial chemistry based on fine organic synthesis as an elementary brick of combinatorial synthesis. In this way, the structure will not be bloated by heteroatoms and pharmacology will receive a simple, clean, high-quality mechanism for the synthesis of structures.

What does deep rational drug design mean? It means the application of modern knowledge to the construction of pharmacological methods and design methods without or together with computer modeling, but necessarily an intelligent approach for deep analysis of the material. For example, statements that computer modeling has an advantage in that it is able to obtain the most highly affinity drugs are not true, because even in the pre-computer era, drugs with maximum affinity were created by analyzing data and deep design based on rational drug design.
For example, the design of GPR55 antagonists based on CBD derivatives involves complex synthesis, which complicates testing a large number of such molecules. It is possible to remove the limiting factor, for this it is necessary to understand the pharmacological scheme of CBD activity, apply this and a number of similar schemes and pharmacological maneuvers to build more accessible pharmacological analogs based on simple initial and simple reactions, pure reactions, inexpensive precursors, with simple methods for obtaining derivatives, within the framework specified above.

The requirements and frameworks are extensive and comprehensive, but there are also many opportunities for implementation. In the course of writing this work, dozens of cores and hundreds of structures were developed that implement various strategies for obtaining agonists and antagonists, complex agonists-antagonists, drugs with special properties, for example, not passing the blood-brain barrier. Also shown in the illustration are substances of different lipophilicity, ability to pass through biomembranes and other properties.
The purpose of such a wide range of forms, qualities and possibilities was the maximum approximation to the required qualities for various groups of drugs - anticancer drugs, drugs to combat autoimmune reactions, for central and purely peripheral drugs, for obtaining water-soluble and water-insoluble drugs, for obtaining drugs that do not leave the organ into which they were introduced, or for obtaining drugs that are well distributed and maximally bioavailable, but do not pass the blood-brain barrier or pass it.
Such pharmacological and physicochemical properties are required for the development of special forms of anticancer drugs, central or peripheral drugs, and, importantly, some properties, such as the inability to penetrate the blood-brain barrier, are extremely useful in the development of non-narcotic drugs that do not give central side effects, which improves their safety and opens up wide opportunities in the market.

In this work, dozens of strategies for obtaining agonists and antagonists, as well as complex agonists-antagonists of GPR55 and CB2 (as related structures) were implemented.
But, nevertheless, the structures remain unlabeled, because to confirm the activity, it is necessary to carry out synthesis and activity studies. This work is only an example of strategies and tactical maneuvers of deep rational design, since there is a chance of error when the supposed agonist will show antagonist activity and vice versa, the supposed antagonist will turn out to be an agonist, the structures are not described, especially since too many expositions were required to describe each structure.

The main messages will be the simplicity of combinatorial chemistry of fine organic structures, implementation of various strategies for constructing agonists and antagonists, deep work on discovering new pharmacological maneuvers in the design of structures, design of an extended spectrum of physicochemical and pharmacological properties. Preliminary edits of toxicity, catabolism, biostability and biolability, bioavailability, penetration of special barriers, saturation and unsaturation of structures, high affinity and activity, ease of synthesis and availability of precursors, purity of reactions (pharmacological organic synthesis), control and spectrum of molecular weight, lipophilicity, compactness of the solution of a pharmacological problem, static and dynamic behavior, change of configurations...

Examples of structures: