Non-narcotic opioids and cannabinoids as potential analgesic agents.

It is known that cannabinoids and opioids have a central analgesic effect. it is also known that they are active and with local application. For example, ointments based on marijuana are active as well as ointment on the basis of rapidly degrading endogenous endorphins and enkephalins.

Such drugs alleviate pain in inflammatory processes, chronic pain, and hypothetically can be effective in cases of injury. But for the full activity of these forms of drugs are not sufficiently active. Overcoming chronic pain is an unresolved issue, despite the development of numerous drugs, various groups and types of actions and other efforts.

In this paper, it is proposed to consider in more detail the possibilities of the drug design in this area, with examples of opioids and cannabinoids, in order to achieve new results at a new level of quality and safety:

Local application provides a precise influence on the process, standard application affects the entire chain of passage of the pain signal, from the point of origin to the point of recognition and perception. If we use drugs that do not cross the blood-brain barrier, but are active opiates or cannabinoids, we can probably get something in between.

The brain and spinal cord will not receive even one-hundredth of the drugs, but the peripheral nervous system is almost open to substances that do not pass through the lipid barrier. In this case, we do not need to worry about the drug not to defund into the bloodstream, for fear of a narcotic effect. We can increase the dose, make a subcutaneous injection, inject the drug intravenously or orally as a tablet form. Without fear of narcotic effects, addiction. Tolerance and dependence can manifest at the peripheral level, but this is in no way compared to the syndrome of drug opiate withdrawal.

Nature has many examples of substances that somehow do not pass the barriers of bioavailability. These are biolabile substances, surface-active substances, substances not absorbed by the digestive system, quaternary ammonium salts that do not cross the blood-brain barrier. There are few natural cannabinoids and opiates among such substances, these are exclusively endogenous cannabinoids and opioids, they are biolabile, and this is a small window of opportunity. But chemical compounds of a similar nature are also scarce, these are topical preparations such as Loperamide (which is not absorbed in the digestive tract) and Quaternary bases of morphine derivatives (acting as laxatives, because they are alkylated in the responsible part of the molecule).

The figure shows examples of a fundamentally new approach to drug design of quaternary bases from this area. These are quaternary bases which probably retain their functionality and activity, but when transformed into tertiary or secondary bases, they are inactivated. For these examples of substances, activity is possible only in the form of quaternary bases. This is a very important quality. because it eliminates the narcotic activity of catabolites.

Also, such substances are characterized by high safety against overdose. As the drug is known, the design of opiates requires a very high-quality and subtle approach; otherwise, overdose and respiratory arrest are possible, even at medium dosages. But substances that do not pass through the blood-brain barrier do not require this complex adjustment during design, this requirement is absent, since even metabolites are not narcotic.

Thus, summing up all possible advantages, we conclude that the substances of this group should be in the libraries of pharmacological companies, chemical companies, among the substances to be screened and developed. This paper shows the basics of design for such applicants. The list is ready to be supplemented with more complex substances with more complex pharmacology. Examples of substances:

As shown in the illustration, in the bulk, the substances are water-soluble, including both cannabinoids and integrated substances. All of them are composed of Quaternary bases, often in a spatially obstructed position, this is a deliberate step, thus reducing the likelihood of incorrect biological activity.

When the quaternary bond is broken, inactive metabolites are mainly formed, the substances also suggest ways of catabolism and excretion from the body. The main necessary parameters for the design of drugs at the initial stage are taken into account and substances are ready for list expansion and development.