Natural Products as Lead Structures

Although a number of biologically active natural products have been indispensable as tools for identification and characterization of pharmacological and potential therapeutic targets, these compounds normally do not satisfy the multiple demands on drugs for therapeutic use (Chapter 6). Thus, although morphine is used therapeutically, it is not an ideal drug, and has to some extent been replaced by a number of analogues showing slightly lower side effects and higher degrees of selectivity for subtypes of opiate receptors (Chapter 19). Prominent examples are the ^-selective opiate agonist, fentanyl, and U50,488, which selectively activates the K-subtype of opiate receptors (Figure I.4).

ryy Q

Fentanyl

U50,488

Tetrahydrocannabinol (THC)

Tetrahydrocannabinol (THC)

Fentanyl

HO CP55,940

HO CP55,940

Cytisine

Cytisine c

Varenicline

Varenicline

Muscimol

THIP (Gaboxadol)

THIP (Gaboxadol)

Trp-Pro-Arg-Pro-Gln-Ile-Pro-

Trp-Pro-Arg-Pro-Gln-Ile-Pro-

Teprotide o

O Voh

W-Succinylproline

O Voh

W-Succinylproline

Captopril

FIGURE 1.4 Chemical structures of fentanyl, U50,488, tetrahydrocannabinol (THC), CP55,940, cytisine, varenicline, muscimol, THIP (gaboxadol), teprotide, N-succinylproline, and captopril.

The main psychoactive constituent of Cannabis sativa, the highly lipophilic tetrahydrocannabi-nol (THC) has been a useful tool for the identification of the two cannabinoid receptors, CBr and CB2-receptor operated by endocannabinoids. Since different preparations of C. sativa have psycho-active effects, health authorities have been reluctant to accept THC and analogues as therapeutic agents for the treatment of pain and other disease-related conditions. This may change with time, as medicinal chemists have synthesized a number of cannabinoid receptor ligands, including the receptor agonist CP55,940, which is markedly less lipophilic than THC (Chapter 19).

The nicotine acetylcholine receptors (nAChRs) have become key targets for therapeutic approaches to treat pain, cognition disorders, depression, schizophrenia, and nicotine dependence. For several reasons, nicotine has limited utility as a therapeutic agent, and a wide variety of nAChR agonists have been synthesized and characterized (Chapter 16). (-)-Cytisine is a naturally occurring toxin acting as a powerful nAChR agonist. Using (-)-cytisine as a lead structure, varenicline was developed as a partial nAChR agonist showing an optimally balanced agonist/antagonist profile for smoking cessation.

Muscimol is another example of a naturally occurring toxin, which has been extensively used as a lead for the design of specific GABA receptor agonists and GABA uptake inhibitors (Chapter 15). Muscimol, which is a 3-isoxazolol bioisostere of GABA, is a constituent of the mushroom Amanita muscaria. Muscimol is toxic, it is metabolically unstable, and it interacts with the different GABA synaptic mechanisms and with a broad range of GABAA receptor subtypes. The cyclic analogue of muscimol, THIP (Gaboxadol) is highly selective for the therapeutically interesting extrasynaptic

GABAa receptors. Gaboxadol is a clinically active nonopioid analgesic and a nonbenzodiazepine hypnotic, which at present is in clinical trials (see also Chapters 15 and 20).

The angiotensin-converting enzyme (ACE) is a zinc carboxypeptidase centrally involved in the regulation of blood pressure and is an important target for therapeutic intervention. Peptide toxins from the Brazilian pit viper, Bothrops jararaca and the synthetic peptide analogue, teprotide, are inhibitors of ACE (Figure I.4), but are not suitable for therapeutic use. Systematic molecular dissection of teprotide led to the nonpeptide ACE inhibitor, N-succinylproline, which was converted into the structurally related and much more potent analogue, Captopril that is now marketed as an effective antihypertensive drug.

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