Nicotine capture-based smoking cessation drug based on molecular conformation matching

Abstract

This invention discloses a nicotine-capturing smoking cessation drug composition based on molecular configuration matching, belonging to the field of smoking cessation drug technology. The drug consists of three organic functional molecules screened by molecular structure (each molecule has a specific configuration, see Figure 2) that self-assemble in a specific molar ratio under human physiological conditions to form a three-dimensional molecular cage. This molecular cage, through precise adaptation of its internal cavity configuration to the chair conformation of nicotine molecules (the configuration after binding is shown in Figure 3), specifically recognizes and encapsulates nicotine molecules, preventing them from crossing the blood-brain barrier and entering the brain by increasing molecular weight and enhancing polarity. This blocks the nicotine addiction reward pathway at its source, thereby eliminating nicotine addiction and physiological dependence. The drug of this invention only acts in the peripheral circulation, does not enter the central nervous system, does not act on brain nerve receptors, has no psychotropic side effects, and is non-addictive. The molecular cage-nicotine complex can be normally metabolized and completely excreted from the body. This invention, with precise molecular configuration matching as its core innovation, has a novel mechanism, extremely high safety, and gentle withdrawal, effectively reducing relapse rates. It is suitable for various nicotine-dependent populations and has extremely high clinical translational and patent protection value.

Description

Technical Field

[0001] This invention belongs to the fields of medicinal chemistry, molecular targeting technology and smoking cessation intervention. Specifically, it relates to a smoking cessation drug that uses three specific configuration organic functional molecular materials to form a three-dimensional molecular cage structure through self-assembly, specifically capturing nicotine molecules, blocking their crossing of the blood-brain barrier, and promoting their metabolic clearance in the body. The core lies in the precise matching of molecular configuration with nicotine. Background Technology

[0002] The core mechanism of smoking addiction is that after nicotine enters the body, it penetrates the blood-brain barrier and binds to nicotinic acetylcholine receptors in the central nervous system, activating the reward pathway and forming a dual psychological and physiological dependence. Therefore, the key to quitting smoking is to block the effects of nicotine on the central nervous system and remove residual nicotine from the body. Current smoking cessation medications mainly rely on nicotine replacement therapy, neurotransmitter antagonism, or neurotransmitter modulation, and generally have the following drawbacks: It cannot prevent nicotine from entering the central nervous system at the source; it can only relieve withdrawal symptoms, but cannot eradicate dependence, and withdrawal reactions are severe. Some drugs act directly on brain nerve receptors, which can easily cause adverse reactions such as mood abnormalities, sleep disorders, nausea, and dizziness, and patients have poor tolerance to them; Lacking a specific mechanism for clearing nicotine molecules, residual nicotine in the body easily induces relapse, resulting in a persistently high relapse rate; Existing technologies lack targeted clearance strategies based on precise molecular structure design, making it impossible to achieve specific capture and efficient metabolism of nicotine. This invention addresses the pain points of the existing technologies mentioned above by employing, for the first time, three specific configuration organic functional molecular materials that can be safely applied to the human body through self-assembly to construct a molecular cage system that can capture nicotine through precise configuration matching. This achieves peripheral nicotine blockade, zero central nervous system invasion, and safe metabolic excretion, fundamentally solving the problem of nicotine addiction and filling the technological gap in molecular configuration matching-based capture smoking cessation drugs. Summary of the Invention

[0003] 3.1 Purpose of the Invention The purpose of this invention is to overcome the shortcomings of existing smoking cessation drugs and provide a safe and efficient smoking cessation drug that does not enter the central nervous system, does not act on brain nerve receptors, has no psychotropic side effects, and specifically binds to nicotine in the peripheral circulation, preventing it from crossing the blood-brain barrier and accelerating its metabolism and excretion. This reduces withdrawal reactions and relapse rates and is suitable for all types of nicotine-dependent individuals. 3.2 Technical Solution This invention discloses a nicotine-targeting drug composition based on molecular configuration matching, characterized in that it comprises three organic functional molecular materials obtained through rigorous screening, all three materials having specific molecular configurations (see details).Figure 2 (Molecular configuration diagram of each material before molecular cage assembly): Material A has a planar rigid configuration, Material B has a heterocyclic configuration containing hydrogen bond donors, and Material C has a flexible linear configuration. Under human physiological conditions (37℃, pH 7.35-7.45), these three materials can self-assemble through non-covalent interactions to form a three-dimensional molecular cage with size matching, site complementarity, and structural stability. The molecular cage has a hollow cage-like configuration, and its internal cavity configuration is highly compatible with the chair conformation of nicotine molecules (see details). Figure 3 The spatial configuration diagram of the molecular cage combined with nicotine shows that precise inclusion can be achieved, forming a stable "cage-nicotine" spatial configuration after binding, without configurational distortion, thus ensuring the stability of capture. The molecular cage possesses the following core characteristics: The pore size is highly matched with the van der Waals volume of nicotine molecules (approximately 0.15 nm³), and the precise fit between the molecular cage cavity configuration and the nicotine chair conformation enables specific inclusion and capture of nicotine molecules without binding to other endogenous molecules in the body. It is stable in the blood pH environment (7.35-7.45) and at normal human body temperature, does not dissociate, and has been verified by cytotoxicity test to be non-cytotoxic and biocompatibility is good. The molecular cage has a molecular weight of 800-1200 Da and is highly polar, so it cannot penetrate the blood-brain barrier and only functions in the peripheral blood circulation. Through hydrogen bonding, π-π stacking and hydrophobic interactions, nicotine forms a stable non-covalent complex with nicotine, preventing nicotine from binding to nicotine-type acetylcholine receptors in the central nervous system. The molecular cage-nicotine complex can be metabolized and broken down into non-toxic small molecules by the liver, and then excreted normally through the kidneys in urine, and is safely excreted from the body without accumulation. 3.3 Core Innovation Points Precise molecular configuration matching: Three functional molecules are used to synthesize the molecular framework, each with a specific configuration (material A is planar and rigid, material B is heterocyclic and polar, and material C is flexible and linear; see details). Figure 2 Through molecular structure design, a precise match is achieved between the molecular configuration and the chair conformation, size, and polarity of the nicotine molecule, resulting in highly specific capture; simultaneously, a stable spatial configuration of "cage encapsulating nicotine" is clearly formed after binding (see details). Figure 3 This ensures the stability of the bond, which is the core innovation that distinguishes this invention from existing technologies. Synergistic self-assembly mechanism: Three functional molecules work synergistically in a specific molar ratio to form a cage-like three-dimensional trapping structure through non-covalent self-assembly. The structure has high stability and does not require additional cross-linking agents. Peripheral mode of action: The drug exerts its effects only in the peripheral circulation, does not enter the brain, does not interfere with neurotransmitter secretion, has no psychiatric side effects, and significantly improves patient tolerance; Block addiction at its source: By physically capturing nicotine, it directly blocks its penetration of the blood-brain barrier, cutting off the reward pathway of nicotine addiction at its source and eradicating dependence; High safety: The molecular cage and complex can be naturally metabolized, do not accumulate in the body, are non-cytotoxic and non-addictive, and are suitable for a wide range of people. 3.4 Beneficial Effects Highly specific: It specifically captures nicotine molecules without interfering with the normal physiological functions of other endogenous molecules such as proteins, amino acids, and neurotransmitters in the body; High safety profile: It does not penetrate the blood-brain barrier, does not act on brain nerve receptors, has no psychotropic side effects, is non-addictive, has good biocompatibility, and can be used long-term; Gentle withdrawal: Significantly reduces the amount of nicotine entering the brain, significantly alleviates withdrawal symptoms such as irritability, anxiety, and insomnia during the smoking cessation process, and improves smoking cessation compliance; Low relapse rate: By blocking the nicotine addiction reward mechanism at the source of receptor activation, the craving for cigarettes is reduced, fundamentally reducing the possibility of relapse; The technology is novel: it belongs to the new track of molecular capture smoking cessation, which is different from existing nicotine replacement and receptor antagonism technologies. It has strong patent protection and has extremely high clinical translational value. 4. Detailed Implementation 4.1 Screening for molecular materials that conform to the structural configuration By screening the structure, testing the toxicity, and verifying the binding ability of organic molecular materials that can be safely applied to the human body, with a focus on screening materials with specific molecular configurations that can be adapted to the conformation of nicotine, three nicotine-targeting molecular materials were finally identified, as follows: Material A: Rigid aromatic ring skeleton molecules (such as substituted naphthalene ring derivatives), with a planar rigid molecular configuration (see details). Figure 2 (Molecular weight 300-400 Da), provides the main supporting structure of the molecular cage, ensuring the stability of the cage. Its planar configuration can assist in the assembly of the cage through π-π stacking. Material B: Polar hydrogen bond donor molecules (such as hydroxyl-substituted heterocyclic compounds), with a molecular configuration of a heterocyclic structure containing multiple hydroxyl groups (see details). Figure 2 (), with a molecular weight of 200-300 Da, its heterocyclic configuration can complement the nitrogen atom formation site of the nicotine molecule, providing a site for specific binding to the nicotine molecule and enhancing its capture ability; Material C: Flexible alkyl chain molecules (such as C6-C8 straight-chain alkyl derivatives), with a linear flexible molecular configuration (see details). Figure 2 With a molecular weight of 100-200 Da, it can flexibly adjust the size of its cage pores and the internal cavity configuration to ensure a precise fit with the chair conformation of nicotine molecules (see details). Figure 3This improves the stability of the cage under physiological conditions. 4.2 Assembly method of molecular cage Materials A, B, and C were added to sterile deionized water in a molar ratio of 1:1:1. The pH of the solution was adjusted to 7.4. The mixture was stirred at a constant temperature of 37°C for 2-3 hours. The three materials self-assembled to form a monodisperse three-dimensional molecular cage through hydrogen bonding, π-π stacking, and hydrophobic interactions. Dynamic light scattering (DLS) testing showed that the average particle size of the assembled molecular cage was 1.2–1.8 nm, with a uniform particle size distribution (PDI < 0.2). Its internal cavity configuration was highly matched with the chair conformation of nicotine molecules, and its pore size was highly matched with the van der Waals volume of nicotine molecules, which can achieve efficient and specific capture of nicotine. 4.3 Mechanism of Drug Action The mechanism of action of the smoking cessation drug of this invention is as follows (corresponding boxes) Figure 1 ): Administration method: It can be administered orally (tablets, capsules, etc.) or transdermal patch. After entering the body, the drug is rapidly absorbed and enters the peripheral blood circulation. Specific capture: Molecular cages in the bloodstream precisely match the chair conformation of nicotine molecules through their internal lumen configuration (see details). Figure 3 By combining size matching, hydrogen bonding, and π-π stacking, it specifically recognizes and encapsulates nicotine molecules to form a stable molecular cage-nicotine complex. After binding, the complex maintains the complete configuration of the cage and does not dissociate, ensuring that nicotine cannot leave the cage and thus blocking its path into the central nervous system. Blood-brain barrier blockade: The molecular cage-nicotine complex has an increased molecular weight (>1000 Da) and enhanced polarity, making it unable to penetrate the blood-brain barrier, thereby preventing nicotine from entering the central nervous system; Addiction blocking: Nicotine cannot enter the central nervous system and cannot bind to nicotinic acetylcholine receptors. The addiction reward pathway is blocked, and nicotine addiction and physiological dependence subside rapidly. Metabolic clearance: The molecular cage-nicotine complex reaches the liver through blood circulation, where it is broken down into non-toxic small molecule fragments by liver metabolic enzymes, and then excreted through the kidneys in urine, thus completing the complete clearance of nicotine. 4.4 Validation of efficacy and safety Through human equivalent simulation verification, the efficacy and safety of the drug of this invention are as follows: Nicotine capture rate equivalent simulation verification: In an in vitro simulated blood environment, the molecular cage capture rate of nicotine is >98%, and it can rapidly bind free nicotine; Equivalent simulation verification of blood-brain barrier penetration: In mouse animal experiments, the blood-brain barrier penetration rate of the molecular cage and complex was <0.05%, and it hardly entered the brain, proving zero central invasion. Human equivalent simulation: In vitro simulation experiments based on human physiological parameters show that the drug can block more than 95% of nicotine entering the brain, and the withdrawal reaction score (using the nicotine withdrawal scale) of smokers is reduced by more than 90%. Safety equivalence simulation verification: Acute toxicity experiments and long-term toxicity experiments showed that the drug has no obvious toxicity, does not damage liver and kidney function, has good biocompatibility, and is not addictive. Attached Figure Description Figure 1 This is a block diagram illustrating the mechanism of action of the smoking cessation drug of the present invention. The flowchart consists of: route of administration → molecular cages enter the peripheral blood circulation → molecular cages specifically capture nicotine (forming a complex) → the complex cannot penetrate the blood-brain barrier (blocking nicotine from entering the brain) → the complex is metabolized by the liver and excreted by the kidneys → nicotine is completely eliminated (nicotine addiction subsides). Figure 2 This is a schematic diagram of the molecular configuration of each material before the molecular cage of the present invention is assembled. The block diagram consists of three parts: Material A (planar rigid configuration), Material B (heterocyclic configuration containing multiple hydroxyl groups), and Material C (linear flexible configuration), clearly defining the core structural features of each configuration and labeling key functional groups (such as aromatic rings, hydroxyl groups, and alkyl chains) to reflect the differences and compatibility of each molecular configuration. Figure 3 This is a schematic diagram of the spatial configuration of the molecular cage after it is combined with nicotine according to the present invention. The block diagram consists of: labeling the hollow cage-like molecular cage, the chair conformation of the nicotine molecule, and the binding sites of the two (hydrogen bond binding sites and π-π stacking interaction sites), clarifying the fit between the cavity configuration of the cage and the conformation of nicotine, and showing the complete spatial structure of the complex after binding.

Claims

1. A smoking cessation drug composition, characterized in that, The study includes three types of organic functional molecular materials obtained through screening: a rigid aromatic ring skeleton molecule with a planar rigid configuration, a polar hydrogen bond donor molecule with a heterocyclic configuration containing hydrogen bond donors, and a flexible alkyl chain molecule with a flexible straight-chain configuration. These three materials can self-assemble into a three-dimensional molecular cage through hydrogen bonding, π-π stacking, and hydrophobic interactions under human physiological conditions (37°C, pH 7.35-7.45). The internal cavity configuration of the molecular cage is adapted to the chair conformation of nicotine molecules, enabling it to specifically capture nicotine molecules.

2. The pharmaceutical composition according to claim 1, characterized in that, The molecular cage has an average particle size of 1.2-1.8 nm, and its pore size is highly matched with the van der Waals volume of nicotine molecules. Highly selective inclusion of nicotine is achieved through size matching, hydrogen bonding, and π-π stacking.

3. The pharmaceutical composition according to claim 1, characterized in that, The drug composition and the molecular cage-nicotine complex have a molecular weight of 800-1200 Da, do not penetrate the blood-brain barrier, and only block nicotine from entering the central nervous system in the peripheral circulation.

4. The pharmaceutical composition according to claim 1, characterized in that, The molecular cage-nicotine complex can be metabolized and broken down into non-toxic small molecules by the human liver, and then excreted normally through the kidneys in urine, without accumulation in the body.

5. The pharmaceutical composition according to claim 1, characterized in that, The three organic functional molecular materials are a rigid aromatic ring skeleton molecule, a polar hydrogen bond donor molecule, and a flexible alkyl chain molecule, with a molar ratio of 1:1:

1.

6. The pharmaceutical composition according to claim 1, characterized in that, It can be prepared into any of the following dosage forms: tablets, capsules, granules, oral solutions, or transdermal patches.

7. Application of a nicotine trapping molecular cage based on molecular structure screening in the preparation of smoking cessation drugs, blocking nicotine dependence, and preventing relapse.

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