The Science Behind the Birth of Kindolor
The pharmaceutical industry has for years focused on finding molecules that are highly specific for single entities (targets) thought to be central for development and expression of particular disease states. However, many diseases have a complex etiology that can be best described as a perturbation of several components of a network normally utilized to perform a physiological function. Evidence continues to mount that such network disturbances will not readily respond to therapeutic interventions directed at a single target.
The technique of Network Pharmacology seeks to identify key points (nodes) within a network that would produce the proper ameliorative effect when targeted simultaneously. This approach allows for effective treatment of complex diseases such as chronic pain.
Employing network pharmacology requires defining the network that needs to be targeted. In the case of Lohocla Research, we wished to focus on the network that initially senses pain and subsequently conducts the resulting pain impulses to the central nervous system (i.e., the peripheral nociceptive system). By choosing this network, we benefited by circumventing the further complexity generated by the entry and distribution of pain signals to various areas of the brain, where subjective perception combines with the physiological pain signal.
The peripheral sensory system is well studied, and its mechanisms are well characterized: the mechanisms that transform painful stimuli into electrical impulses, the mechanisms that conduct these impulses to the spinal cord and brain, and the mechanisms that transmit the pain signals from the peripheral neurons to the neurons of the CNS (i.e., the spinal cord and brain). Also known is that development of chronic pain is a maladaptive process in which certain nodes of the peripheral sensory network are detrimentally up- or down-regulated. This knowledge allowed us to identify which nodes we should attempt to target simultaneously in order to generate a true network effect and, thereby, an effective treatment for chronic pain.
Knowing the targets we wished to address, we used structural information about both these targets and drug molecules to design and synthesize specific, multi-target compounds through a process called “rational drug design.” The targets that we chose to address in the maladapted peripheral sensory system were the voltage-sensitive sodium channels, the glutamate (NMDA subtype) receptors, and the delta opioid receptors. In the process of development of chronic pain, it is known that
- certain voltage-sensitive sodium channels are up-regulated, leading to neuronal hyperexcitability;
- the NMDA receptors are up-regulated, again leading to hyperexcitability of the sensory neurons as well as to sensitization of pain-sensing entities such as the TRP V1-containing nociceptors, which respond to changes in temperature and to pressure; and
- delta opioid receptors, which are not related to the addictive effects of opiates, are up-regulated and serve the function of dampening pain signals in the sensory neurons as well as in spinal cord and brain. Up-regulation of the delta opioid receptors involves their transport to the neuronal membrane in an attempt to counter the hyperexcitability of the perturbed network, but this response does little good without an agonist to activate these opioid receptors.
Accordingly, the drug molecule that we designed and synthesized
- inhibited voltage sensitive sodium channels, particularly Nav1.7;
- inhibited the NMDA receptors, particularly those containing the NR2B subunit; and
- acted as an agonist (activator) of the delta opioid receptors.
We designed our compound so that it would not enter the brain to any consequential extent, thereby preventing side effects mediated by the central nervous system. In addition, because our targets were primarily confined to the sensory neurons in the periphery, we also were able to protect other peripheral organs from adverse effects.
And thus, Kindolor was born.